BRPI0817909B1 - Methods of obtaining and preparing a diastereomerically pure composition, compounds, and method of producing said compounds - Google Patents

Abstract

METHODS OF OBTAINING AND PREPARING A SUBSTANTIALLY DIASTEREOMERICALLY PURE COMPOSITION, COMPOUNDS, AND METHOD FOR PRODUCING SUCH COMPOUNDS. The present invention relates to methods of synthesizing intermediates useful for the synthesis of halichondrin B analogues.

Description

Related Orders

[0001] This Order claims Priority for U.S.S.N. 60/997,625, filed October 3, 2007, the complete contents of which are hereby incorporated by reference.

Background of the Invention

[0002] The present invention relates to a method for the synthesis of halichondrin B and analogues thereof having pharmaceutical activity, such as anticancer or antimitotic (mitosis blocking) activity. B-1939 (also known as E7389 or eribulin), a halichondrin B analogue, has been reported to be useful for the treatment of cancer and other proliferative disorders including melanoma, fibrosarcoma, leukemia, colon carcinoma, ovarian carcinoma, breast carcinoma, osteosarcoma , prostate carcinoma, lung carcinoma, and ras-transformed fibroblasts.

[0003] Halichondrin B is a structurally complex marine natural product containing multiple chiral centers in an extended carbon structure. Due to the limited availability of halichondrin B from natural sources, methods for the synthesis of halichondrin B are of value for the purposes of developing the full medicinal potential of halichondrin B analogues. A method for the synthesis of halichondrin B analogues was published in 1992 ( Aicher, T.D. and others, J. Am. Chem. Soc. 114:3162-3164 ). A method for the synthesis of Halichondrin B Analogs, including B-1939, has been described in WO 2005/118565 (EISAI COMPANY, LTD.). The method described in WO 2005/118565 has several practical advantages over the method described by Aicher, including, but not limited to, the discovery of several crystalline intermediates that allowed increased quality control, reproducibility, and productivity. However, these advantages, several limiting chromatographic purifications remained, particularly with respect to the C14-C26 fragment. For example, the C14-C26 fragment contains 4 chiral centers at C17, C20, C23, and C25 which requires chromatography to control the quality of this fragment. More specifically, the installation of the C25 chiral center does not occur with high selectivity and could not be practically enhanced due to a lack of late crystalline intermediates in the synthesis of C14-C26.

[0004] What is needed is a more efficient, less costly, more practical method for the synthesis of halichondrin B analogues, in particular B-1939.

summary

[0005] The present invention relates to a method for the synthesis of halichondrin B analogues, such as B-1939, from (-)-quinic acid according to the process illustrated in Scheme 1, below. The method introduces several new and crystalline intermediates that greatly improve the stereochemical quality of the synthesized compounds and reduce the need for chromatographic steps. Unlike the previously described methods, the currently claimed method is substantially more suitable for pharmaceutical manufacturing.

[0006] The invention also pertains to the new intermediates described here.

[0007] WO 2005/118565 described a method for making halichondrin B analogues, such as B-1939, which included synthetic routines for (1) making the compound of formula Ia from (-)-quinic, and for (2) making the compound of formula Ia from (-)-quinic. ) to produce B-1939 from compound AG. Both synthetic routines are suitable for use in the method of the present invention, and are incorporated herein by reference.

[0008] The method of the present invention differs from the method described in WO 2005/118565 in the process of synthesizing compound AH from compound AA. In particular, the present invention describes highly effective methods for generating the C25 chiral center, marked with an asterisk (*) in the relevant compounds in Scheme 1, by an equilibration process and selectively crystallizing the C25 isomer by means of an alpha-methylated nitrile. . In the method described in WO 2005/118565, compound AH is synthesized by adding a methyl group to compound AG, as shown above. This reaction generates the C25 chiral center. The product of that reaction is a mixture of diastereomers with every possible configuration around that chiral center. Chromatography can be used to partially isolate the AH compound from the diastereomer mixture, as described in WO2005/118565; however, the remaining diastereomers of the AH compound result in unwanted impurities in subsequent reaction steps, impurities that can only be removed through further purification procedures.

[0009] Unlike the previously described methods of synthesizing halichondrin B analogues, the method of the present invention involves the formation of the C25 chiral center at an early stage in the synthesis of the AH compound. Several of the methylated intermediates, including compound AD and compound AF, are crystallizable. By crystallizing one or more of the methylated intermediates in accordance with the methods of the present invention, one can produce a composition comprising compound AH that is substantially diastereomerically pure. For example, compound AC can be methylated to produce compound AD. When compound AD is produced, the C25 chiral center is produced, the same chiral center described with respect to compound AH. When this reaction takes place, a diastereomeric mixture is produced with every possible stereomeric configuration around that chiral center. Although the methylation itself occurs with low stereoselectivity, surprisingly, the desired diastereomer of compound AD stereoselectively crystallizes. However, the undesired C25 stereoisomer can be epimerized under conditions from which the desired C25 stereoisomer crystallizes. In this way, the production and quality of the C25 stereoisomer can be enhanced by crystallization-induced dynamic resolution (CIDR).

[00010] Several other synthetic routinely produced intermediates from compound AD to compound AH can also be crystallized from reaction mixtures, resulting in an even higher purity composition of compound AH than could be produced by the previously described methods. In particular, compound AF is a crystalline compound, while the corresponding unmethylated compound AE requires chromatography for purification. Compound AF can be synthesized from compound AD or it can be synthesized by methylating compound AE. Removing the chromatographic steps from the processes used to synthesize the halichondrin B analogs dramatically increases production and product reproducibility, while decreasing production cost and time. The present method also allows one to resolve difficult-to-resolve chiral centers at considerably early points in the process, even as early as the production of compound AH and compound AL B-1939 is adequately synthesized from compound AI using methods such as those described in WO/2005/118565.

em que: z é uma ligação simples ou dupla, contanto que quando z for uma ligação dupla, X2 seja C e Y1 seja hidrogênio; e contanto que quando z for ligação simples, X2 seja CH ou O; X1 é O, S, ou CN, contanto que quando X1 for CN ou S, X2 seja O; Y1 é um haleto, hidrogênio ou O-L2, ou ausente quando X2 for O; e L1 e L2 são independentemente selecionados de hidrogênio e um grupo de proteção, ou L1 e L2 juntamente são um grupo de proteção, contanto que quando X1 for CN, L1 seja ausente; e sais dos mesmos. A invenção também pertence às composições de compostos de fórmula (I) que são substancialmente livres de diastereômeros, bem como compostos de fórmula (I).[00011] In one embodiment, the invention pertains, at least in part, to a method of obtaining a substantially diastereomerically pure composition comprising a compound of formula (I). The method includes crystallizing the compound of formula (I) from a mixture of diastereomers under appropriate crystallization conditions such that a substantially diastereomerically pure composition comprising a compound of formula (I) is formed. The compound of formula (I) is:

wherein: z is a single or double bond, provided that when z is a double bond, X2 is C and Y1 is hydrogen; and provided that when z is single bond, X2 is CH or O; X1 is O, S, or CN, provided that when X1 is CN or S, X2 is O; Y1 is a halide, hydrogen or O-L2, or absent when X2 is O; and L1 and L2 are independently selected from hydrogen and a protecting group, or L1 and L2 together are a protecting group, provided that when X1 is CN, L1 is absent; and salts thereof. The invention also pertains to compositions of compounds of formula (I) which are substantially free of diastereomers, as well as compounds of formula (I).

e o composto de fórmula (Ib) é:

em que L1a e L1b são independentemente selecionados de hidrogênio e um grupo de proteção, ou L1a e L1b juntamente são um grupo de proteção divalente, contanto que L1a de fórmulas (Ia) e (Ib) seja igual e L1b de fórmulas (Ia) e (Ib) seja igual. Quando L1a ou L1b for um grupo de proteção, ele será preferivelmente selecionado do grupo que consiste em C1-C6 alquil éteres, aril (C1-C6) alquil éteres, silil (C1- C1O) éteres, C1-C6 alquila ésteres, C1-C6 acetais cíclicos, C2-C7 cetais cíclicos, e carbonatos cíclicos. O método inclui reagir o composto de fórmula (Ia) sob condições de alquilação para formar uma mistura que compreende o composto de fórmula (Ib) e diastereômeros do mesmo; e cristalizar o composto de fórmula (Ib) a partir da mistura, sob condições de cristalização apropriadas.[00012] In another embodiment, the invention also pertains to a method of preparing a diastereomerically pure composition of a compound of formula (Ib) from a compound of formula (Ia), wherein the compound of formula (Ia) is:

and the compound of formula (Ib) is:

where L1a and L1b are independently selected from hydrogen and a protecting group, or L1a and L1b together are a divalent protecting group, provided that L1a of formulas (Ia) and (Ib) is equal and L1b of formulas (Ia) and (Ib) be equal. When L1a or L1b is a protecting group, it is preferably selected from the group consisting of C1-C6 alkyl ethers, aryl (C1-C6) alkyl ethers, silyl (C1-C1O) ethers, C1-C6 alkyl esters, C1- C6 cyclic acetals, C2-C7 cyclic ketals, and cyclic carbonates. The method includes reacting the compound of formula (Ia) under alkylating conditions to form a mixture comprising the compound of formula (Ib) and diastereomers thereof; and crystallizing the compound of formula (Ib) from the mixture under appropriate crystallization conditions.

em que: c é uma ligação simples ou dupla, contanto que quando c for uma ligação dupla m seja 0 e Y3 seja 0 ou CHCo2-L3, e contanto que quando c for uma ligação simples m seja 0 ou 1 e Y3 seja CH2O-L3, CH2CO2-L3 ou CH2CH2O-L3; Y2 é C1-C7 sulfanato, O-L4 ou um haleto; L4 é hidrogênio ou um grupo de proteção; e L3 e L5 são cada qual independente hidrogênio ou um grupo de proteção, ou L3 e L5 juntamente são um grupo de proteção, ou um sal do mesmo. A invenção também pertence às composições de compostos de fórmula (II) que são substancialmente livres de diastereômeros, bem como compostos de fórmula (II).[00013] In another embodiment, the invention pertains, at least in part, to a method of obtaining a substantially diastereomerically pure composition comprising a compound of formula (II). The method includes crystallizing the compound of formula (II) from a mixture of diastereomers under appropriate second crystallization conditions, such that a substantially diastereomerically pure composition comprising a compound of formula (II) is formed. The compound of formula (II) is:

where: c is a single or double bond, provided that when c is a double bond m is 0 and Y3 is 0 or CHCo2-L3, and provided that when c is a single bond m is 0 or 1 and Y3 is CH2O- L3, CH2CO2-L3 or CH2CH2O-L3; Y2 is C1-C7 sulfonate, O-L4 or a halide; L4 is hydrogen or a protecting group; and L3 and L5 are each independently hydrogen or a protecting group, or L3 and L5 together are a protecting group, or a salt thereof. The invention also pertains to compositions of compounds of formula (II) which are substantially free of diastereomers, as well as compounds of formula (II).

em que: L6 é hidrogênio ou um grupo de proteção; e sais dos mesmos.[00014] In yet another embodiment, the invention also pertains to compounds of formula (III):

where: L6 is hydrogen or a protecting group; and salts thereof.

L6a, L6b, e L6c são cada qual grupos de proteção, ou um sal do mesmo, e em que a composição é substancialmente livre de diastereômeros.[00015] In yet another embodiment, the invention also pertains to a composition comprising a compound of formula (IIIa):

L6a, L6b, and L6c are each protecting groups, or a salt thereof, and wherein the composition is substantially diastereomer-free.

[00016] Furthermore, the invention also pertains to a composition comprising a compound selected from the group consisting of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II) ), (Ha), (IIb), (III) and (IIIa). The invention also pertains to each of the compounds described herein.

Detailed Description

[00017] The present invention pertains, at least in part, to methods and intermediates for the preparation and crystallization of intermediates and other compounds useful in the synthesis of halichondrin B and its analogues.

A. Definitions

[00018] In order that the present invention may be more easily understood, certain terms are first defined. Additional definitions are set out throughout the detailed description.

[00019] The term "acetyl" refers to both acyl groups (e.g. -C(=0)-CH3) and C1-C8 alkyl substituted carbonyls (e.g. -C-(=O)-(C1 -C7)alkyl)). Preferably, the acetyl group is acyl.

[00020] The term "alkyl" refers to saturated hydrocarbons having one or more carbon atoms, including straight chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.), alkyl groups cyclic (or "cycloalkyl" or "alicyclic" or "carbocyclic" groups) (e.g., cyclopropyl, cyclopentyl, cyclohexyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, sec-butyl, isobutyl, etc.), and alkyl-substituted alkyl groups (e.g., alkyl-substituted cycloalkyl groups and cycloalkyl-substituted alkyl groups). The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous to alkyls, but containing at least one carbon-carbon double or triple bond respectively.

[00021] The term "alkoxy" refers to alkyl groups bonded to the remainder of the molecule through an oxygen atom. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Alkoxy groups can be straight-chain or branched. Preferred alkoxy groups include methoxy.

[00022] The term "heterocyclic group" refers to closed ring structures analogous to carbocyclic groups in which one or more of the carbon atoms in the ring is an element other than carbon, for example, nitrogen, sulfur, or oxygen. Heterocyclic groups can be saturated or unsaturated. Additionally, heterocyclic groups (such as pyrrolyl, pyridyl, isoquinolyl, quinolyl, purinyl, and furyl) may have aromatic character, in which case they may be referred to as "heteroaryl" or "heteroaromatic" groups. Exemplary heterocyclic groups include, but are not limited to, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, pyrimidine, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, naptridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.

[00023] The term "amine" or "amino," refers to the unsubstituted or substituted portion of the formula -NRaRb, where Ra and Rb are each independently hydrogen, alkyl, aryl, or heterocyclyl, or Ra and Rb, taken together with the nitrogen atom to which they are attached form a cyclic moiety having from 3 to 8 ring atoms. Thus, the term amino includes cyclic amino moieties such as piperidinyl or pyrrolidinyl groups, unless otherwise stated.

[00024] With respect to connectivity, an "arylalkyl" group, for example, is an alkyl group substituted with an aryl group (e.g., phenylmethyl (i.e., benzyl)). An "alkylaryl" moiety is an aryl group substituted with an alkyl group (e.g. p-methylphenyl (i.e. p-tolyl)). Thus, the term imidazolyl-alkyl refers to an alkyl group substituted with an imidazolyl moiety.

[00025] The term "sulfanate" refers to moieties of the formula: R-SO2-O-, wherein R is C1-C4 alkyl or C6-C8 aryl. Examples of sulphanates include methanesulfanate (mesylate), trifluoromethanesulfanate (triflate) p-toluenesulfanate (tosylate), and benzenesulfanate (benzylate).

pode representar butano ou buteno.[00026] As used in the description and drawings, an optional single/double bond is represented by a solid line along with a second dotted line, and refers to a covalent bond between two carbon atoms which may be the single bond or a double bond. For example, the structure:

can represent butane or butene.

[00027] The term "protecting group" refers to the moieties that can be cleaved from the compound to yield a hydroxy group, a thiol group, a carboxylic acid group, or other functional group that a person skilled in the art wishes to protect. . Generally, protecting groups are selected such that they resist cleavage during reactions focused on other portions of the molecule. Protecting groups can be selected so that they are acid labile (eg, cleavable in the presence of acid), base labile (eg, cleavable in the presence of base), or otherwise selectively cleavable. Protecting groups are well known to those skilled in the art. Examples of suitable protecting groups can be found, for example, in "Protective Groups in Organic Synthesis," 3rd edition, John Wiley & Sons, Inc.

[00028] Examples of protecting groups include, but are not limited to, C1-C12 alkylcarbonyl moieties, C1-C6 alkyl, C1-C15 alkyl silyl moieties (e.g., moieties that form alkyl silyl ethers when bonded to an adjacent oxygen), aryl( C1-C6) alkyls, carbonates, and C1-C6 alkoxy-(C1-C6)alkyls (e.g. methoxymethyl).

[00029] Examples of C1-C1O alkyl silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, or triisopropylsilyl (e.g., trimethylsilyl ether, triethylsilyl ether, t-butyldimethylsilyl ether, t - butyldiphenylsilyl ether, or triisopropylsilyl ether when considered together with an adjacent oxygen). Preferably, the alkyl silyl protecting group is t-butyldimethylsilyl ether.

[00030] Examples of C1-C6 alkyl protecting groups include methyl and t-butyl (eg methyl ethers and t-butyl ethers when considered together with an adjacent oxygen).

[00031] Examples of aryl (C1-C6) alkyl protecting groups include 3,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, or trityl (e.g., 3,4-dimethoxybenzyl ether, p-methoxybenzyl ether, benzyl ether or trityl ether when considered together with an adjacent oxygen).

[00032] Compounds with two or more groups to be protected (e.g., hydroxy and/or thiol groups) can be protected together using a protecting group that bonds to both of the hydroxy and/or thiol groups for which the protection is desired. These protecting groups are also referred to herein as "divalent protecting groups." Examples of divalent protecting groups that protect two hydroxy and/or thiol groups include, but are not limited to, C1C6 acetals, C2-C6 ketals, and cyclic carbonates. Examples of cyclic protecting groups include, but are not limited to, acetonide, benzylidine, and, preferably, cyclohexylidine. Examples of protecting groups that protect two hydroxy or thiol groups include those shown below. Arrows indicate where the moiety is attached to hydroxy or thiol groups in the compound:

[00033] The term "acceptable salts" refers to salts of the compounds of the invention that are acceptable for the methods of the invention, for example, the synthesis of intermediates of halichondrin B analogues.

[00034] Compounds of the invention which are acidic in nature are capable of forming a wide variety of base salts. Chemical bases that can be used as reagents to prepare acceptable base salts of those compounds of the invention that are acidic in nature are those that form base salts with such compounds. Such base salts include, but are not limited to, those derived from such pharmaceutically acceptable cations such as alkali metal cations (e.g. potassium and sodium) and alkaline earth metal cations (e.g. calcium and magnesium), addition salts of water or ammonium soluble amines such as N-methylglucamine-(meglumine), and alkanolammonium and other pharmaceutically acceptable base salts of organic amines. Base addition salts of compounds of the invention which are acidic in nature can be formed with cations by conventional methods.

[00035] The term "antisolvent" includes organic solvents in which the compound of interest is not substantially soluble therein. Examples of anti-solvents for compounds of the present invention of formula (II) include non-polar solvents such as heptane.

[00036] The term "alkylating reagent" refers to a reagent which is capable of adding an alkyl group, preferably a methyl group, to the particular organic compounds described herein including, but not limited to, compounds of formula (Ia). Preferably, the alkylating reagent is a C1-C4 alkyl halide (preferably MeI) or a sulfonate.

[00037] The term "proper alkylation condition" refers to conditions that are selected so that an alkylation reaction is capable of being carried out. These conditions include an aprotic solvent (eg, tetrahydrofuran, toluene, or t-butyl methyl ether) and a base (eg, a metal amide or a metal alkoxide). Examples of bases that can be used under the alkylation conditions include, but are not limited to, LDA, KHMDS, and potassium t-butoxide.

[00038] The language "appropriate crystallization conditions" refers to conditions that are selected so that the desired diastereomer of a particular compound is crystallized, preferably a compound of formula (I) or (Ib). Examples of solvent systems that can be used to effect this crystallization include, but are not limited to, heptane and mixtures of heptane with one or more co-solvents, such as, but not limited to, tert-butyl methyl ether and isopropanol. The ratio of heptane to tert-butyl methyl ether or isopropanol is selected so that the desired diastereomer is crystallized. The ratio can range from about 5:1 to about 3:1, and is preferably about 4:1. Appropriate conditions may also include the addition of a base. Examples of such bases include C1-C6 alkoxides (e.g. t-butyl oxide or isopropoxide). Alternatively, other solvent systems can also be used, such as combinations of a protic solvent and an anti-solvent.

[00039] The language "appropriate second crystallization conditions" refers to conditions that are selected so that the desired diastereomer of a particular compound is crystallized, preferably a compound of formula (II) or (Ha). Examples of suitable second crystallization conditions for crystallizing compounds of formula (II) and/or (Ha) include dissolving the compound in a polar solvent (e.g. MTBE) and optionally adding an anti-solvent to precipitate the compound.

[00040] The term "contact" refers to any interaction between two or more compounds that results in a chemical reaction, such as, but not limited to, the creation or cleavage of one or more chemical bonds.

[00041] The language "mixture of diastereomers" refers to compositions comprising two or more diastereomers.

[00042] The term "protic solvent" refers to a solvent that contains a dissociable H+ or a group capable of forming hydrogen bonds (eg, hydroxyl or amine group). Examples are water, methanol, ethanol, formic acid, hydrogen fluoride and ammonia. Preferred protic solvents include alcohols, such as isopropanol.

[00043] The language "substantially diastereomerically pure composition" refers to compositions whose ratio of a particular compound to compound with the opposite stereochemistry at the chiral center indicated with an asterisk in Scheme 1 is at least about 8:1 or more , at least about 10:1 or more, at least about 15:1 or more, at least about 20:1 or more, or, preferably, at least about 30:1 or more. Diastereomeric purity can be enhanced using multiple kinetic resolutions or crystallization-induced dynamics. It can also be enhanced by repeated recrystallizations.

[00044] The language "substantially no chromatography" refers to synthesis methods that use 4 or less, 3 or less, 2 or less, 1 or less, or no chromatography steps. Preferably, the term refers to methods of synthesis that do not require preparative HPLC steps.

[00045] Certain abbreviations and acronyms are used here. As definições para estas abreviações e acrônimos estão listadas abaixo: ACNAcetonitrilo AcOHÁcido acético CIDRResolução dinâmica induzida por cristalização DBUDiazabicicloundecano DCMDiclorometano DIBALHidreto de diisobutilalumínio DMEDimetoxietano DMFDimetilformamida ESIInjeção por rotação de elétron Et3NTrietilamina EtOAcAcetato de etila EtOHEtanol FDAAdministração de alimento e fármaco HPLCCromatografia líquida de pressão elevada IPAIsopropanol iPr2NEtDiisopropiletilamina KHMDSPotássio- Potassium hexamethyldisilazane KOtButerc-butoxide LDA Lithium diisopropyl amide LRMSELow resolution mass spectrometry Methyl meIIodide MeOHMethanol MsC1Mesyl chloride (methanesulfonyl chloride; CH3SO2Cl) MTBEMethyl tert-butyl ether MsO-Mesylate (methanesulfanate) NaOEtEthoxide Sodium NaOMeMethoxide NaOMeMethoxide sodium NBmosuccimide NISN-iodosuccinimide NMRNuclear magnetic resonance Ph3PTriphenyl phosphine TBDPSC1 Tert-butyl diphenyl silyl chloride TBMEMethyl tert-butyl ether TBSterc-b utildimetil silila TBSC1Cloreto de terc-butildimetil silila TBSOTfTrifluorometanossulfonato de terc-butildimetilsilila tBuOKTerc-butóxido de potássio TEATrietilamina TESOTfTrifluorometanossulfanato de trietilsilila TsClCloreto de tosila (cloreto de p-toluenossulfonila) TfO-Triflato (trifluorometanossulfanato) Tf2OAnidrido tríflico (CF3SO2)2O TsO-Tosilato (p- toluenesulfanate) THF Tetrahydrofuran TsOH p-Toluenesulfonic acid TosMICIToluenesulfonylmethyl isocyanide TrtTrityl (Triphenylmethyl) B. Compounds

em que: z é uma ligação simples ou dupla, contanto que quando z for uma ligação dupla, X2 seja C e Y1 seja hidrogênio; e contanto que quando z for ligação simples, X2 seja CH ou O; X1 é O, S, ou CN, contanto que quando X1 for CN ou S, X2 seja O; Y1 é um haleto, hidrogênio ou O-L2, ou ausente quando X2 for O; e L1 e L2 são independentemente selecionados de hidrogênio e um grupo de proteção, ou L1 e L2 juntamente são um grupo de proteção, contanto que quando X1 for CN, L1 seja ausente; e sais dos mesmos. A invenção também pertence aos compostos de fórmula (I).[00046] In one embodiment, the invention pertains to a compound of formula (I):

wherein: z is a single or double bond, provided that when z is a double bond, X2 is C and Y1 is hydrogen; and provided that when z is single bond, X2 is CH or O; X1 is O, S, or CN, provided that when X1 is CN or S, X2 is O; Y1 is a halide, hydrogen or O-L2, or absent when X2 is O; and L1 and L2 are independently selected from hydrogen and a protecting group, or L1 and L2 together are a protecting group, provided that when X1 is CN, L1 is absent; and salts thereof. The invention also pertains to compounds of formula (I).

[00047] In one embodiment, L1 and/or L2 are each independently a silyl ether, a C1-C8 alkyl ether, an acyl group (-C(=O)CH3), or acetyl. Preferably, X1 is oxygen. Preferably, L1 and L2 may represent the same protecting group attached to the molecule through both the O of X2 when Y1 is O-L2 and X1. Examples of such protecting groups include, but are not limited to, C1-C6 cyclic acetals, C2-C6 cyclic ketals, and cyclic carbonates. In another embodiment, L1 and L2 are bonded to a single divalent protecting group. Examples of divalent protecting groups include acetonides, benzylidines, and preferably, cyclohexylidine. In certain embodiments, when both L1 and L2 are protecting groups, L1 and L2 when taken together can form a pentane, hexane, or pyran ring and bond to X1 through X2 through a single carbon atom. Preferably, when Y1 is O-L2; X1 is O or S; L1 and L2 together form a protecting group which is a C4-C7 alkyl ring with a ring member covalently bonded to the O of O-L2 and to X1. In one embodiment, X2 is CH, Y1 is O-L2, and X1 is O.

[00048] In another embodiment, when Y1 is a halide, it is fluoride, chloride, iodide, or, preferably, bromide. In another further embodiment, L1 is acetyl.

[00049] In another embodiment, when z is a double bond, Y is hydrogen, and X2 is C.

[00050] In another further embodiment, X1 is oxygen and L1 is a protecting group (when considered together with X1) selected from the group consisting of C1-C6 alkyl ether, aryl (C1-C6) alkyl ether, C1C6 ester, and a silyl (C1-C10) ether.

[00051] In another additional embodiment, X2 is oxygen, when z is a single bond. In another additional embodiment, L1 is hydrogen. In another further embodiment, L1 is a protecting group selected from a glycoside, C1-C6 alkyl, C1-C6 acetyl, and a C1-C6 ester.

em que L1a e L1b são hidrogênio, grupos de proteção independentemente selecionados, ou juntamente um grupo de proteção divalente. Em uma outra modalidade, L1a e L1b são cada qual grupos de proteção selecionados de C1-C6 alquil éteres, aril (C1-C6) alquil éteres, silil (C1-C10) éteres, C1-C6 alquila ésteres, C1-C6 acetais cíclicos, C2-C7 cetais cíclicos, e carbonatos cíclicos.[00052] Preferably, the compound of formula (I) is a compound of formula (Ib):

where L1a and L1b are hydrogen, independently selected protecting groups, or together a divalent protecting group. In another embodiment, L1a and L1b are each protecting groups selected from C1-C6 alkyl ethers, aryl (C1-C6) alkyl ethers, silyl (C1-C10) ethers, C1-C6 alkyl esters, C1-C6 cyclic acetals. , C2-C7 cyclic ketals, and cyclic carbonates.

[00053] In another embodiment, the invention pertains to a composition comprising a compound of formula (Ib), wherein the composition is substantially diastereomerically pure. In another embodiment, the ratio of compounds of formula (Ib) to compounds having the opposite stereochemistry at the asterisked chiral center is at least about 8:1 or more, at least about 20:1 or more, or, preferably, at least about 30:1 or more.

ou um sal do mesmo.[00054] In another embodiment, the compound of formula (I) is selected from the group consisting of:

or a salt thereof.

em que: c é uma ligação simples ou dupla, contanto que quando c for uma ligação dupla m seja 0 e Y seja O ou CHCO2-L3, e contanto que quando c for uma ligação simples m seja 0 ou 1 Y3 seja CH2O-L3, CH2CO2-L3 ou CH2CH2O-L3; Y2 é C1-C7 sulfanato, O-L4 ou um haleto; L4 é hidrogênio ou um grupo de proteção; e L3 e L5 são cada qual independente hidrogênio ou um grupo de proteção, ou L3 e L5 juntamente são um grupo de proteção, ou um sal do mesmo.[00055] In another embodiment, the invention pertains to a compound of formula (II):

where: c is a single or double bond, provided that when c is a double bond m is 0 and Y is O or CHCO2-L3, and provided that when c is a single bond m is 0 or 1 Y3 is CH2O-L3 , CH2CO2-L3 or CH2CH2O-L3; Y2 is C1-C7 sulfonate, O-L4 or a halide; L4 is hydrogen or a protecting group; and L3 and L5 are each independently hydrogen or a protecting group, or L3 and L5 together are a protecting group, or a salt thereof.

[00056] Examples of Y2 include halides, for example, fluoride, chloride, bromide, or preferably, iodide. In another embodiment, Y2 is O-L4. Examples of L4 include hydrogen. In another embodiment, c is a double bond. Examples of Y3 when c is a double bond include CHCO2-L3. Examples of L3 groups include C1-C6 alkyl, for example methyl.

[00057] In another embodiment, c is a single bond. Examples of Y3 when c is a single bond include CH2CH2-OL3. In another embodiment, L3 and L5 can be linked to form a C1-C6 cyclic acetal or a C2-C7 cyclic ketal. In another embodiment, Y3 is CH2CO2-L3 and L3 is C1-C10 alkyl, C4-C10 aryl-C1-C6 alkyl, or C4-C10 aryl. In another further embodiment, Y2 is a halide, eg iodide.

[00058] In another embodiment, the invention pertains to a composition comprising a compound of formula (II), wherein the composition is substantially diastereomerically pure. In another embodiment, the ratio of compounds of formula (II) to compounds with the opposite stereochemistry at the asterisked chiral center is at least about 8:1 or more, at least about 20:1 or more, or, preferably, at least about 30:1 or more.

Composto AFComposto AP, e

Composto AQ ou um sal do mesmo.[00059] In another further embodiment, the compound of formula (II) is selected from the group consisting of: <<DRAW-CODE> Compound NACompound AO

AF compound AP compound, and

Compound AQ or a salt thereof.

[00060] The invention also pertains to compositions comprising the compounds shown above substantially free of diastereomers.

[00061] In another embodiment, the invention also pertains to a compound of formula (Ia):

[00062] In another embodiment, the compound of formula (IIa) is substantially free of diastereomers, for example, a compound having the opposite stereochemistry at the chiral carbon indicated with an asterisk in the above formula. In one embodiment, the invention pertains to a substantially diastereomerically pure composition comprising a compound of formula (IIa), wherein the ratio of compounds of formula (IIa) to compounds having the opposite stereochemistry at the chiral center marked with the asterisk is at least about 8:1 or more, at least about 20:1 or more, or, preferably, at least about 30:1 or more.

em que: L6 é hidrogênio ou um grupo de proteção; ou um sal aceitável do mesmo. Em uma modalidade, a invenção pertence a uma composição substancialmente diastereomericamente pura que compreende um composto de fórmula (III), em que a relação de compostos de fórmula (III) para os compostos com a estereoquímica oposta no centro quiral marcado com o asterisco é de pelo menos cerca de 8:1 ou mais, pelo menos cerca de 20:1 ou mais, ou, preferivelmente, pelo menos cerca de 30:1 ou mais.[00063] The compound of formula (IIa) is particularly important because while it is crystalline, the corresponding unmethylated intermediate is not crystalline and requires purification by chromatography. The invention also pertains to compounds of formula (Ha) in crystalline form. In another embodiment, the invention pertains to a compound of formula (III):

where: L6 is hydrogen or a protecting group; or an acceptable salt thereof. In one embodiment, the invention pertains to a substantially diastereomerically pure composition comprising a compound of formula (III), wherein the ratio of compounds of formula (III) to compounds having the opposite stereochemistry at the chiral center marked with the asterisk is at least about 8:1 or more, at least about 20:1 or more, or, preferably, at least about 30:1 or more.

[00064] In another embodiment L6 is hydrogen or, when considered together with the oxygen to which it is attached, a silyl C1-C1O ether. Examples of such C1 -C10 silyl ethers include, but are not limited to, trimethylsilyl ether, triethylsilyl ether, t-butyldimethyl silyl ether, t-butyldiphenylsilyl ether, or triisopropylsilyl ether.

Composto ARComposto AH.[00065] In another embodiment, the compound of formula (III) is:

AR Compound AH Compound.

[00066] The invention also pertains to a composition comprising the compounds shown above substantially free of diastereomers.

em que L6a, L6b, e L6c são cada qual grupos de proteção, ou um sal do mesmo. Em uma outra modalidade, a invenção pertence a uma composição que compreende o composto de fórmula (IIIa) em que a composição é substancialmente livre de diastereômeros (por exemplo, compostos com a estereoquímica oposta no centro quiral indicado com um asterisco na fórmula (IIIa) acima).[00067] In another embodiment, the invention pertains to compounds of formula (IIIa):

wherein L6a, L6b, and L6c are each protecting groups, or a salt thereof. In another embodiment, the invention pertains to a composition comprising the compound of formula (IIIa) wherein the composition is substantially free of diastereomers (e.g. compounds having the opposite stereochemistry at the chiral center indicated with an asterisk in formula (IIIa)). above).

(Id) em que L1a e L1b são independentemente selecionados de hidrogênio e um grupo de proteção, ou L1a e L1b juntamente são um grupo de proteção divalente, ou um sal do mesmo. C. Métodos[00068] The invention also pertains, at least in part, to compounds of formula (Id):

(Id) wherein L1a and L1b are independently selected from hydrogen and a protecting group, or L1a and L1b together are a divalent protecting group, or a salt thereof. C. Methods

[00069] In one embodiment, the invention pertains to a method of obtaining a substantially diastereomerically pure composition comprising a compound of formula (I). The method includes crystallizing the compound of formula (I) from a mixture of diastereomers under appropriate crystallization conditions, so that a substantially diastereomerically pure composition comprising a compound of formula (I) is formed. The mixture of diastereomers is preferably the mixture of compounds of formula (I) with compounds of formula (Ie), wherein said compound of formula (Ie) is:

[00070] In one embodiment, the substantially diastereomerically pure composition comprises a ratio of compounds of formula (I) to compounds of formula (Ie) of at least about 8:1 or more, of at least about 10:1 or more, at least about 20:1 or more, or, preferably, at least about 30:1 or more. In order to increase the diastereomeric purity of the compound of formula (I), further recrystallizations of the compound under similar appropriate conditions may be conducted.

[00071] Appropriate crystallization conditions are selected so that the desired diastereomer is crystallized. Examples of solvent systems that can be used to accomplish this crystallization include, but are not limited to, heptane/tert-butyl methyl ether and heptane/isopropanol. Appropriate conditions may also include the addition of a base. Examples of such bases include C1-C6 alkoxides (e.g. t-butyl oxide or isopropoxide).

[00072] Alternatively, other solvent systems may also be used, such as combinations of a protic solvent (e.g. an alcohol, e.g. isopropanol) and an anti-solvent (e.g., non-polar organic solvent, e.g. heptane ).

e o composto de fórmula da fórmula (Ib) é:

em que L1a e L1b são independentemente selecionados de hidrogênio e um grupo de proteção, ou L1a e L1b juntamente são um grupo de proteção divalente, contanto que L1a de fórmulas (Ia) e (Ib) sejam iguais e L1b de fórmulas (Ia) e (Ib) sejam iguais. O método inclui reagir o composto de fórmula (Ia) sob condições de alquilação para formar uma mistura que compreende o composto de fórmula (Ib) e diastereômeros do mesmo; e cristalizar o composto de fórmula (Ib) a partir da mistura, sob condições de cristalização apropriadas.[00073] In another embodiment, the invention also pertains to a method of synthesizing the compound of formula (Ib) from a compound of formula (Ia) by contacting a compound of formula (Ia) with an alkylating reagent under appropriate alkylation conditions. The compound of formula (Ia) is:

and the compound of formula of formula (Ib) is:

where L1a and L1b are independently selected from hydrogen and a protecting group, or L1a and L1b together are a divalent protecting group, provided that L1a of formulas (Ia) and (Ib) are the same and L1b of formulas (Ia) and (Ib) are equal. The method includes reacting the compound of formula (Ia) under alkylating conditions to form a mixture comprising the compound of formula (Ib) and diastereomers thereof; and crystallizing the compound of formula (Ib) from the mixture under appropriate crystallization conditions.

[00074] In order to increase the diastereomeric purity of the compound of formula (Ib), further recrystallizations of the compound under similar appropriate conditions can be conducted. Preferably, mixing of diastereomers after two or more crystallizations results in a ratio of compounds of formula (Ib) to compounds whose opposite stereochemistry around the chiral center indicated with the asterisk above in formula (Ib) should be at least about 8:1 or more, at least about 10:1 or more, at least about 20:1 or more, or at least about 30:1 or more.

[00075] In yet another embodiment, the invention also pertains, at least in part, to a method of obtaining a substantially diastereomerically pure composition comprising a compound of formula (I). The method includes contacting the mixture of diastereomers with a base at an appropriate temperature so that a substantially diastereomerically pure composition comprising a compound of formula (I) is formed. Examples of bases that can be used in the method include bases known in the art, such as amide bases, metal alkoxides and KHMDS. The base may be present in any amount so that the desired diastereomer is formed. Preferably, the base is present in substoichiometric amounts (e.g., less than one equivalent). In another further embodiment, the appropriate temperature is less than about -30°C. In another embodiment, the compound of formula (I) is a compound of formula (Ib).

[00076] If kinetic resolution of the stereocenter is desired, the compound of formula (I) or (II) may be treated with substoichiometric amounts of a strong base (e.g. an amide base, e.g. KHMDS) at low temperatures (e.g. less than about -30°C). Once the reaction has taken place, compounds of formula (I) or (II) can be isolated from an appropriate crystallization solvent system and recrystallized. Examples of solvent systems that can be used include, but are not limited to, heptane, heptane/t-butyl methyl ether, and heptane/isopropanol.

[00077] Alternatively, crystallization-induced dynamic resolution (CIDR) can also be used to enhance the diastereomeric purity of compounds of formula (I) and/or (II). For example, compounds of formula (I) and/or (II) can be treated with a weak base, such as an alkoxide, (e.g. potassium t-butyloxide or potassium isopropoxide) in a crystallization solvent system. appropriate. Examples of suitable crystallization solvent systems include combinations of a protic solvent (eg isopropanol) and an anti-solvent (eg heptane) at non-cryogenic temperatures to provide purified compounds of formula (I) or (II).

[00078] In another embodiment, the invention pertains to a method of obtaining a substantially diastereomerically pure composition comprising a compound of formula (II). The method includes crystallizing the compound of formula (II) from a mixture of diastereomers under appropriate crystallization conditions such that a substantially diastereomerically pure composition comprising a compound of formula (II) is formed. In one embodiment, the composition comprises a ratio of compounds of formula (II) to compounds of formula (IIb) of at least about 8:1 or more, at least about 10:1 or more, at least about 20: 1 or more, or, preferably, at least about 30:1 or more. The compound of formula (IIb) is:

[00079] In order to increase the diastereomeric purity of the compound of formula (II), further recrystallizations of the compound under similar appropriate conditions can be conducted.

[00080] In another embodiment, the invention also pertains to a method of synthesizing a compound of formula (IIa) from a compound of formula (Ib). The method includes selectively crystallizing a compound of formula (Ib) under appropriate crystallization conditions; and reacting the compound of formula (Ib) under appropriate conditions so that a compound of formula (IIa) is formed. Preferably, the compound of formula (Ha) is formed using substantially no chromatography. The compound of formula (Ib) can be reacted under appropriate conditions to form a compound of formula (IIa), after it has been diastereomerically purified using recrystallization. Furthermore, appropriate conditions may comprise dissolving a crystallized compound of formula (Ib) in a solvent before reacting it under appropriate conditions to form a compound of formula (IIa).

[00081] Suitable conditions for the synthesis of compounds of formula (IIa) from compounds of formula (Ib) are described, for example, in schemes 5, 6, 8, 9, and 10. Methods for selectively crystallizing a compound of formula (I) or (Ib) from a mixture of diastereomers under appropriate crystallization conditions have been described above.

[00082] The invention also pertains, at least in part, to a method of synthesizing a compound of formula (IIIa) from a compound of formula (IIa). The method includes crystallizing a compound of formula (IIa) under appropriate second crystallization conditions; reacting the compound of formula (Ha) under appropriate conditions so that a compound of formula (IIIa) is formed.

[00083] Examples of suitable second crystallization conditions for crystallizing compounds of formula (IIa) include dissolving the compound in a polar solvent (eg MTBE) and optionally adding an anti-solvent to precipitate the compound. Examples of anti-solvents that can be used include heptane. Preferably, the compound of formula (IIa) is reacted under appropriate conditions to form a compound of formula (IIIa), after it has been crystallized.

[00084] In another embodiment, the invention also pertains to a method of synthesizing a compound of formula (IIIa) from a compound of formula (Ib). The method includes selectively crystallizing a compound of formula (Ib) under appropriate crystallization conditions; and reacting the compound of formula (Ib) under appropriate conditions so that a compound of formula (IIIa) is formed. Preferably, the compound of formula (IIIa) is formed using substantially no chromatography.

[00085] The compound of formula (Ib) can be reacted under appropriate conditions to form a compound of formula (IIIa), after being diastereomerically purified using recrystallization. Furthermore, appropriate conditions may comprise dissolving a crystallized compound of formula (Ib) in a solvent before reacting it under appropriate conditions to form a compound of formula (IIIa).

em que cada qual dentre L7a, L7b, L7c, L7d, e L7e são cada um grupo de proteção ou hidrogênio. Exemplos de L7a incluem fenila. Exemplos de L7b incluem metila. Exemplos de L7c e L7d incluem TBS. Exemplos de L7e incluem hidrogênio.[00086] In another embodiment, the invention pertains to a method of synthesizing compounds of formula (IV). The method includes crystallizing a compound of formula (Ib) from a mixture of diastereomers under appropriate crystallization conditions as described above; reacting the selectively crystallized compound of formula (Ib) with appropriate reagents so that a compound of formula (IV) is synthesized. The compound of formula (IV) is:

wherein each of L7a, L7b, L7c, L7d, and L7e are each a protecting group or hydrogen. Examples of L7a include phenyl. Examples of L7b include methyl. Examples of L7c and L7d include TBS. Examples of L7e include hydrogen.

[00087] Examples of suitable reagents that can be used to synthesize compounds of formula (IV) from a compound of formula (Ib) include those described in schemes 5, 6, 8, and 9 to form a compound of formula ( IIIa). Methods that can be used to convert a compound of formula (IIIa) to a compound of formula (IV) are described in greater detail in WO/2005/118565, incorporated herein by reference in their entirety.

[00088] The compound of formula (Ib) can be reacted under appropriate conditions to form a compound of formula (IV), after it has been diastereomerically purified using recrystallization. Furthermore, appropriate conditions may comprise dissolving a crystallized compound of formula (Ib) in a solvent before reacting it under appropriate conditions to form a compound of formula (IV).

[00089] In another embodiment, the compound of formula (IV) is formed in greater than about 50% production, greater than about 60% production, or more than about 70% production from of a compound of formula (Ib).

[00090] In another embodiment, the invention also pertains to compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb) ), (III), (IIIa), (IV), (V), or otherwise described herein. The invention also pertains to compositions comprising compounds of any of these formulas substantially free of diastereomers. The invention also pertains to each of the intermediates and processes described herein.

[00091] In another embodiment, the invention pertains to compositions comprising compounds described herein substantially free of diastereomers, for example compounds having the opposite stereochemistry at the chiral carbon indicated with the asterisk in scheme 1. The invention also pertains to methods for use these compounds to synthesize compounds of formula (IV), B-1939, or other analogues of halichondrin B.

[00092] The invention pertains, at least in part, to methods and intermediates for converting compounds of formula (I) into compounds of formula (III). Compounds of formula (III) may also be converted to compounds of formula (IV) and/or halichondrin B or analogues thereof.

[00093] Compounds of formula (III) can be synthesized by the methods described herein. The invention pertains, at least in part, to all compounds and intermediates described herein and the processes for synthesizing the compounds and intermediates. Conversion of compound 2-1 to a compound of formula (Ib)

[00094] Compounds of formula (Ib) can be synthesized from compounds of formula 2-1, as shown in scheme 2:

scheme 2

[00095] Compound 2-1 can be converted to compound (Ib). In scheme 2, L1a and L1b are protection groups. Examples of protecting groups include, but are not limited to, C1-C6 alkyl ethers, aryl (C1-C6) alkyl ethers, silyl (C1-C10) ethers, C1-C6 alkyl esters, C1-C6 cyclic acetals, C2-C7 cyclic ketals, and cyclic carbonates. Examples of R2 include hydrogen, C1-C6 alkyl groups (e.g. methyl, t-butyl, etc.), C4-C10 aryl (e.g. phenyl), and C4-C10 aryl-C1-C6 alkyl (e.g., benzyl). Examples of R3 and R4 include CH3 and OCH3' respectively or R3 and R4 taken together may be (-CH2CH2)2O.

[00096] Compound 2-1 can be converted to compound 2-4 through the use of an appropriate reducing agent. Examples of such reducing agents include, but are not limited to, aluminum hydrides and borohydrides (e.g., BH3, AlH3, LIbH4, LiAlH4, NaBH4, NaAlH4, ZnBH4).

[00097] The hydroxyl group of compound 2-4 can be transformed into a leaving group such as, but not limited to, a sulfanate (eg, MsO-, TsO-, TfO-) or halide by methods described in the literature. Subsequent treatment with a cyanide source (e.g. KCN or NaCN) results in the formation of compound 2-5.

[00098] Alternatively, compound 2-4 can be transformed into compound 2-5 by oxidizing the hydroxyl group to the aldehyde by methods described in the literature.

[00099] The conversion of the aldehyde to the nitrile can be accomplished with appropriate reagents such as, but not limited to, dimethyl phosphorocyanidate/samarium iodide. Compound 2-5 can be alkylated in a suitable solvent, for example an aprotic solvent such as tetrahydrofuran, toluene, TBME and subsequently treated with a strong base such as a metal amide or metal alkoxides (e.g. LDA , KHMDS, or KO1Bu) and an appropriate alkyl halide (e.g., X-Me) or sulfanate to provide a compound of formula (Ib).

[000100] Alternatively, compound 2-1 can be converted to compound 2-7 by methods known in the art. Examples of such methods include, but are not limited to, treatment with N,O-dimethylhydroxylamine/trimethylaluminum hydrochloride. Compound 2-7 can be converted to the compound of formula (Id) by treatment with an appropriate carbon-nucleophile. Examples of such nucleophiles include, but are not limited to, alkyl Grignard reagents.

[000101] Alternatively, oxidation of compound 2-4 to the aldehyde followed by the addition of an alkyl Grignard or other carbon-nucleophile provides a secondary alcohol.

[000102] Oxidation using known methods results in the formation of the compound of formula (Id). Compounds of formula (Ib) can be synthesized, for example, by treating the compound of formula (Id) with TosMIC in the presence of metal alkoxides such as NaOEt and KOtBu (J. Org. Chem. 42(19), 3114 -3118, (1977)). Alternatively, the compound of formula (Id) can be transformed into the compound of formula (Ib) using reagents such as, but not limited to, dimethyl phosphorocyanidate/samarium iodide. Conversion of (-)-quinic acid to a compound of formula (Id)

[000103] Alternatively a compound of formula (Id) may also be synthesized as shown in scheme 3.

[000104] In scheme 3, L1a and L1b are protecting groups, as described in scheme 2. L2b and L2c are also protecting groups such as, but not limited to, cyclic acetals (X = O and/or S), cyclic ketals (X = O and/or S), and cyclic carbonates (X=O).

[000105] The synthesis of commercially available (-)-quinic acid compound 3-9 has been described previously (WO/2005/118565). Compound 3-9 can be reduced with DIBAL or other reagents known in the art, such as borohydrides and aluminum hydrides, to provide lactol 3-10. Lactol 3-10 can be transformed using a Wittig or Julia olefination to provide compound 3-11. Deprotection followed by double bond migration and Michael addition generate compound (Id).

[000106] More specifically, a Wittig addition can be performed using MeC(OL2b)(OL2c)CH2CH2PPh3 (prepared in situ), in a polar solvent (e.g. THF, MeOH, or DMF) at a temperature ranging from 0 °C at 50°C. Sequential acid-catalyzed reactions (e.g., deprotection, migration, and Michael addition) can be carried out with an acid such as TsOH or HCl in a polar solvent (e.g., THF, or acetone) at a temperature ranging from 10 to 30 °C. °C for about two to four hours. Alternatively, Michael migration and addition can also be carried out with a base such as NaOMe in a polar solvent (eg THF or MeOH). Conversion of compound 4-1 to a compound of formula (I)

[000107] As shown in Scheme 4, compounds of formula 41 (diastereomeric mixture) can undergo isomerization and crystallization to provide compounds of formula (I).

Scheme 4

[000108] In scheme 4, z is a single or double bond, provided that when z is a double bond, X2 is C and Y1 is hydrogen; and provided that when z is single bond, X2 is CH or O; X1 is O, S, or CN, provided that when X1 is CN or S, X2 is O; Y1 is a halide, hydrogen or O-L2, or absent when X2 is O; and L1 and L2 are independently selected from hydrogen and a protecting group, or L1 and L2 together are a protecting group, provided that when X1 is CN, L1 is absent.

[000109] Diastereomers of formula 4-1 can be converted to compounds of formula (I) by treatment with substoichiometric amounts of amide bases (e.g. KHMDS) at low temperatures (e.g. less than about -30°C). °C). Once rinsed, compounds of formula (I) can be isolated and recrystallized from suitable solvent crystallization systems, such as, but not limited to, heptane/t-butyl methyl ether and heptane/isopropanol.

[000110] Alternatively crystallization-induced dynamic resolution (CIDR) can also be used to selectively crystallize compounds of formula (I). For example, diastereomers of formula 4-1 can be treated with a base, such as an alkoxide, (e.g., t-butyloxide or isopropoxide) in an appropriate solvent crystallization system. Examples of suitable crystallization solvent systems include combinations of a protic solvent (eg, isopropanol) and an anti-solvent (eg, heptane) at non-cryogenic temperatures to provide purified compounds of formula (I). Conversion of a compound of formula (Ib) to compound 5-13 Scheme 5

[000111] In Scheme 5, L1a and L1b are as described above in Scheme 2. L1d is a suitable protecting group, for example, C1-C6 alkyl ether, aryl (C1-C6) alkyl ether, C1-C6 ester, or a silyl (C1-C10) ether.

[000112] Compounds of formula (Ib) can be deprotected by various methods known in the art, depending on the nature of L1a and L1b. Examples of deprotection reactions include, but are not limited to, hydrogenation, reduction, oxidation, base-induced deprotection, and acid-induced deprotection. One skilled in the art would be able to choose an appropriate technique based on techniques recognized in the art (see, for example, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc).

[000113] Once L1a and L1b have been removed, the deprotected compound 5-12 can be converted to compound 5-13 by treating compound 5-12 with 2-acetoxy-2-methylpropionyl bromide, catalytic water, in a solvent aprotic such as acetonitrile. The resulting intermediate can be treated with a base (e.g. diazabicycloundecane (DBU)) to provide compound 5-13.

[000114] Alternatively, compound 5-12 can be transformed to compound 5-13 using a multi-step process. The process involves selectively activating a hydroxyl group such as a halide, MsO-, TsO-, or TfO- and protecting the remaining hydroxyl group. Examples of suitable protecting groups for this step include L1d groups such as C1-C6 alkyl ethers, aryl (C1-C6) alkyl ethers, C1-C6 esters, and silyl (C1-C10) ethers. The intermediate can be transformed to compound 5-13 using previously described methods. Conversion of compound 5-13 to compound 6-16 Scheme 6

[000115] In Scheme 6, L1d is hydrogen or a protecting group, C1-C6 alkyl ether, aryl (C1-C6) alkyl ether, C1-C6 ester, or a silyl (C1-C1O) ether). L1c can be hydrogen or a protecting group, such as, but not limited to, a glycoside, C1-C6 alkyl, or a C1-C6 ester. X2 and X3 can each be oxygen or hydroxy.

[000116] Oxidative cleavage of the olefin of compound 5-13 can be carried out using ozone in a suitable solvent (eg methanol) at temperatures below 0°C. The ozone adduct can be prepared using literature methods to provide compound 6-14, where X2 and X3 are each carbonyl or hydroxy. Alternatively, a metal oxide (e.g., osmium tetroxide or potassium permanganate and sodium periodate) can also be used to provide compound 6-14, where X2 and X3 are each carbonyl.

[000117] When X2 and X3 are each carbonyl, they can be reduced to give compound 6-14, wherein X2 and X3 are each hydroxy. Deprotection of L1 can be accomplished using literature methods (eg potassium carbonate in methanol) to provide compound 6-15. Compound 6-15 can be treated with NaIO4 to provide compound 6-16, where L1c is H. Alternatively, compound 6-16 can comprise a glycoside (e.g., L1c is C1-C3 alkyl protecting group, for example methyl) which may be added using methods known in the art, such as methanol in the presence of an acid catalyst.

[000118] shown. Examples of R2 include hydrogen, C1-C6 alkyl groups (e.g. methyl, t-butyl, etc.), C4-C1O aryl (e.g. phenyl), and C4-C1O aryl-C1-C6 alkyl (e.g. benzyl). L1a and L1b are protection groups as described above. Examples of L1c include hydrogen and protecting groups such as glycosides, C1-C6 alkyl and C1-C6 acetyl.

[000119] Compound 2-1 can be transformed to compound 7-17d as described in Schemes 5 and 6. Treatment of compound 7-17d with TosMIC and isomerization/crystallization provides compound 6-16 as shown in Schemes 2 and 4. Conversion of compound 5-16 to compound 7-20 Scheme 8

[000120] Compound 8-20 can be prepared from 6-16 as shown in Scheme 8. In Scheme 8, L1c is hydrogen or a protecting group as previously described; L5 is C1-C10 alkyl, C4-C10 aryl-C1-C6 alkyl, or C4-C10 aryl; and Y is sulfonate or halide.

[000121] When L1c is not hydrogen, the ether is hydrolyzed using literature methods to provide lactol (6-16, L1c = H). Lactol (616, L1c = H) is converted to compound 8-18 by an olefination reaction such as an established Wittig reaction, a Wadsworth-Horner-Emmons reaction, or a Julia olefination. Wittig olefination can be performed with a stabilized ylide such as Ph3PCHCO2L5 in polar solvent (eg, THF, MeOH, or DMF) at an appropriate temperature (eg, -78°C to 50°C). The Wadsworth-Horner-Emmons olefination can be carried out using a stabilized ylide (e.g. (MeO)2POCH2CO2L5) in a polar aprotic solvent (e.g. THF, or ACN) at an appropriate temperature (e.g. -78°C at 25°C) in the presence of a suitable base (e.g. tBuOK, NaH, or LiCl/tertiary amines (e.g. DBU, iPr2NEt, Et3N)).

[000122] Variations in these conditions are known in the art. For example, for variations in the Wadsworth-Horner-Emmons olefination see Org. react 25, 73-253, (1977) and Tetrahedron Lett. 25, 2183 (1984). In addition, Julia olefination can be carried out in a polar aprotic solvent (e.g. THF, DME or a halogenated solvent, e.g. CH2Cl2) in the presence of alkyl sulfone (e.g. alkyl(benzothiazol-2-ylsulfonyl)acetate) and suitable base (eg, BuLi, LDA, KHMDS, or DBU) at an appropriate temperature (eg, -78°C to 25°C). Variations in these conditions will be evident from the literature on Julia olefination (see, Org. Biomol. Chem. 3, 1365-1368, (2005); Synlett, 26-28, (1998)).

[000123] Compound 8-19 can be obtained from compound 8-18 by means of catalytic hydrogenation, which can be carried out in the presence of a metal catalyst (e.g. palladium (Pd/C) or platinum (PtO2) ) in a polar solvent (e.g. EtOAc, MeOH). Preferably, the reaction is carried out under an atmosphere of hydrogen, with a pressure ranging from 4 kPa (0.04 bar) to 110 kPa (1.10 bar).

[000124] The hydroxyl group of 8-19 can be converted to a leaving group (e.g. MsO-, TsO-, TfO-) providing 8-20, using a suitable sulfonyl anhydride or sulfonyl chloride (e.g. MsCl, TsCl, or Tf2O) in a polar aprotic solvent (eg, THF or a halogenated solvent (eg, CH2Cl2)) in the presence of a suitable base (eg, Et3N).

[000125] Optionally, the output group of 8-20 can be converted to a halide. This reaction can be carried out in the presence of a halogenating reagent (eg, NaI, or NaBr) in a polar solvent (eg, DMF or acetone). Alternatively, the transformation of the hydroxyl group to the halide can be carried out using

[000126] In scheme 9, another method of converting compound 6-15 to compound 8-20 is shown. In Scheme 9, R9a and R9b are hydrogen, C1-C6 alkyl or taken together are a carbonyl group; Y2 is sulfonate or halide; and Y3 is O, OL3, or CHCO2-L3 where L3 is hydrogen or a protecting group.

[000127] As shown in Scheme 9, compound 8-20 can be prepared from compound 6-15 using literature methodology for the protection of 1,2 diols. Treatment of the neopentyl hydroxyl of compound 9-21 (using methods described in Scheme 8) provides compound 9-22. Deprotection of compound 9-22 using literature methods provides a diol. Treatment of this diol with a reagent such as sodium periodate provides the aldehyde 9-23 (Y3 = O). Treatment of aldehyde 9-23 as described in Scheme 8 provides compound 8-20. Conversion of compound 7-17b to 8-20

[000128] Alternatively, compound 7-17b can be converted to compound 8-20 as shown in scheme 10. In scheme 10, R2 includes C1-C6 alkyl such as methyl, ethyl, and tert-butyl; R10a and R10b are hydrogen, C1-C6 alkyl or taken together are a carbonyl group; Y is sulfonate or halide; and Y3 is O, OL3, or CHCO2-L3. L3 is hydrogen or a protecting group.

[000129] Compound 7-17b can be transformed to compound 10-17f selectively by protection of the 1,2-diol and a subsequent functional group transformation of the neopentyl hydroxyl group into a sulfanate or halide. Selective protection of 1,2-diol can be accomplished with an aldehyde, ketone, acetal, or a carboxyl chloride (eg, DMP, cyclohexanone, MeOPhCHO, or Ph3P) in the presence of an acid catalyst. The transformation of the functional group of the neopentyl hydroxyl group to a sulfanate or halide was previously described above in Scheme 8. Compounds 10-17g and 10-22 can be prepared in a similar manner previously described in Scheme 2. Deprotection of the diol protecting group using literature procedures followed by treatment with sodium periodate gives the 10-23 (Y = O). A Wittig, Horner-Wadsworth-Emmons, or Peterson type olefination is then followed with hydrogenation to provide compound 8-20. D. Chemical Examples Example 1: Synthesis of Compound AD from Compound AC Scheme 11

[000130] Compound AC (1 weight, 1 volume, 1 equivalent) was dissolved in THF (1.80 volume) and cooled to -75°C. KHMDS (0.50 M solution in toluene, 6.60 volume, 1.10 equivalent) was added at a rate so that the internal temperature did not exceed -65°C. Upon complete addition, stirring was continued at -75°C for 30 minutes. A solution of MeI (0.188 volume, 1.01 equivalent) in THF (0.50 volume) was added at a rate such that the internal temperature did not exceed -65°C. Upon complete addition, stirring was continued at -75°C for 1 hour. KHMDS (0.50 M solution in toluene, 0.60 volume, 0.10 equivalent) was added at a rate such that the internal temperature did not exceed -70°C and stirring was continued at -75°C for more 2.5 hours. Under vigorous stirring, 20 wt% aqueous NH4Cl (1.50 wt, 1.9 equivalent) was added at a rate such that the internal temperature did not exceed -55°C. Upon complete addition, the resulting mixture was allowed to warm to -20°C. Water (1.50 volume) was added and the mixture was also heated to 0°C. The biphasic mixture was transferred to a preparation vessel (reactor was washed with MTBE (0.40 volume)) and vigorous stirring was continued for 2 minutes. The aqueous layer was excluded and the organic layer was washed with water (2.0 volume). The organic layer was concentrated and residual solvents and water were azeotropically removed with heptane (1.50 volume x 2) to provide the crude product as a yellow solid (1.1 weight, dr=4.4:1). The crude (1.1 weight) was suspended in heptane-MTBE (4:1 volume/volume, 5.0 volume) and heated to 80°C. The resulting solution was: 1) cooled to 70°C for 1 hour; 2) held at 70°C for 0.5 hour; 3) cooled to 65°C for 0.5 hour (precipitation started); 4) held at 65°C for 0.5 hour; 5) cooled to 60°C for 0.5 hour; 6) held at 50°C for 0.5 hour; 7) cooled to room temperature and stirring was continued for 40 hours. The crystals were collected by filtration, washed with heptane (1 volume x 2) and dried under N 2 /vacuum to give compound AD as a light brown powder (0.69 wt, 0.66 equivalents, dr=34:1). The mother liquor was concentrated to provide an epimeric mixture (The AS compound) as a yellow solid (epimeric mixture, 0.38 wt., dr AD compound: epimer =1:2.2). Example 2: Diastereomeric Purification of Compound AD from Compound AS. Scheme 12

[000131] Each of the following methods was used in the reaction shown in Scheme 12 to convert the unwanted C25 epimer to the desired C25 isomer, using stereoselective deprotonation-protonation or crystallization-induced dynamic resolution (CIDR).

[000132] Method 1: Compound AS (1 weight, 1 volume, dr = 1:2.2) was dissolved in toluene (2.6 Volume) and cooled to -20°C. KHMDS (0.50 M solution in toluene, 3.4 volume, 0.60 equivalent) was added at a rate such that the internal temperature did not exceed -16°C. Upon complete addition, stirring was continued at -20°C for 15 minutes. Under vigorous stirring, 20 wt% aqueous NH4Cl (1.0 wt, 1.3 equivalent) was added at a rate such that the internal temperature did not exceed -15°C. After 5 minutes, the mixture was allowed to warm to 0°C. The organic layer was separated, washed with water (2.0 volume) and concentrated. Residual solvents and water were azeotropically removed with heptane (3.0 volume x 2) to provide the crude product as a solid-yellow oil mixture (dr=2.6:1). The crude was suspended in Heptane-MTBE (5:1, volume/volume, 3.0 volume) and heated to 80°C. The resulting clear solution was cooled to room temperature (23°C) for 3 hours (precipitation started at 45°C). Crystals were collected by filtration, washed with: 1) heptane-MTBE (5:1 volume/volume, 1.0 volume); 2) heptane (1.0 volume) and dried under N 2 /vacuum to give compound AD as white powder (0.31 wt, 0.31 equivalent, 0.08 equivalent). The mother liquor was concentrated to provide compound AS (0.69 wt., dr=1:1).

[000133] Method 2: Compound AS (1 weight, 1 volume, dr=1:1) was dissolved in heptane-MTBE (5:1 volume/volume, 2.0 volume) and KHMDS (0.50 M solution in toluene, 0.40 volume, 0.07 equivalent) was added at 23°C. Stirring was continued for 10 minutes and the mixture was cooled to 0°C. AD compound (0.0001 weight, 0.0001 equivalent) was added and stirring was continued for a further 30 minutes (increased precipitation). 20 wt% aqueous NH4Cl (0.20 wt, 0.26 equivalent) was added under vigorous stirring. The resulting mixture was diluted with EtOAc (2.0 volume) to dissolve the precipitation of compound AD. The organic layer was separated, washed with water (1.0 volume) and concentrated. Residual solvents and water were azeotropically removed with heptane (5 volumes x 2) to provide the crude product as a solid-yellow oil mixture (dr=2.3:1). The crude was suspended in heptane-MTBE (3:1 volume/volume, 1.5 volume) and heated to 80°C. The resulting clear solution was cooled to 20°C for 3 hours (precipitation started at 50°C). The crystals were collected by filtration, washed with heptane-MTBE (4:1 volume/volume, 1 volume), and dried under N2/vacuum to provide compound AD as a white powder (0.22 weight, 0.22 equivalent, 0 .04 equivalent).

[000134] Method 3 (CIDR): Compound AS (1 weight, 1 volume, dr=1:5) was dissolved in heptane (5 volume) at 23°C. t-BuOK (1.0M solution in THF, 0.29 volume, 0.10 equivalent) was added and stirring was continued for 10 minutes. Precipitations were collected by filtration, washed with heptane (10 volume), and dried to provide compound AD as light brown powder (0.36 wt, 0.36 equivalent, dr=7.3:1, filtrate dr=3.7: 1).

[000135] Method 4: Compound AS (1 weight, 1 volume, 1 equivalent, dr=1:1.7) was dissolved in toluene (5.0 Volume) and cooled to -70-75°C. KHMDS (0.5M solution in toluene, 0.500 equivalent, 2.88 volume, 2.53 weight) was added while maintaining an internal temperature below -65°C. The resulting mixture was cooled to -70-75°C again and stirring was continued at -70-75°C for 4 hours. 20 wt% NH4Cl (aqueous solution, 2.00 wt) was added while maintaining an internal temperature below -60°C. Upon complete addition, the mixture was allowed to warm to 0°C over a period of 1.5 to 2 hours. MTBE (4.00 volume, 2.96 weight) and water (4.00 volume, 4.00 weight) were stirred with stirring and the resulting biphasic mixture was allowed to divide. The organic layer (dr=6.5:1) was separated, washed sequentially with: 1) 20 wt% citric acid (aqueous solution, 1.0 wt); 2) water (3.00 volume); 3) water (3.00 volume) and partially concentrated to ~2 volume under vacuum. The residue was subjected to solvent exchange with heptane (6.00 volume x 2, partial concentration to ~2 volume each time, under vacuum) and diluted with heptane-IPA (6:1 volume/volume, 3.5 volume). The mixture was heated to 60°C, cooled to 15 to 20°C over 4 hours, and again stirred at 15 to 20°C overnight. The crystals were collected by filtration, rinsed with heptane-IPA (9:1 volume/volume, 2.0 volume) and dried under N 2 /vacuum to provide compound AD (0.4 wt, 0.4 equivalent, dr=57 :1) as light brown powder. 1H NMR (500 MHz, hCDC): δ 4.40-4.44 (1H, m), 4.30 (1H, dd, J=6.5, 3.5 Hz), 4.09 (1H, dd , J=6.5, 3.0 Hz), 3.72-3.77 (1H, m); 3.37 (1H, dd, J=10.0, 6.5 Hz), 2.91-2.99 (1H, m), 2.35-2.39 (1H, m), 2.07- 2.12 (1H, m), 1.97-2.03 (1H, m), 1.96 (1H, dd, J=14.0, 4.0 Hz), 1.82 (1H, d, J=12.0 Hz), 1.58-1.70 (5H, m), 1.50-1.58 (6H, m), 1.42-1.49 (1H, m), 1.32 -1.40 (2H, m), 1.29 (3H, d, J=7.0 Hz), 1.11-1.20 (1H, m) 13 C NMR (125 MHz, CDCl 3 ): δ 122, 95, 110.58, 78.29, 76.28, 75.92, 75.81, 72.16, 68.34, 43.80, 40.51, 37.61, 34.52, 29.85, 28.92, 27.24, 25.33, 24.24, 23.84, 22.50, 18.55 LRMS (ESI) m/z found 370.15 [M+Na]+ Melting point 123°C Example 3: Synthesis of compound AJ from compound AD Scheme 13

[000136] Compound AD (1 weight, 1 volume) was suspended in AcOH (5.00 volume, 31 equivalent) at 20°C. 1.00M aqueous HCl (2.48 volume, 1.00 equivalent) was added and stirring was continued at 20°C for 5 hours. The reaction mixture was cooled to 0°C and 50 wt% aqueous NaOH (2 wt, 8 equivalent) was added while keeping the internal temperature below 10°C. Heptane-MTBE (2:1 volume/volume, 10.0 volume) was added and vigorous stirring was continued for 3 minutes. The organic layer was excluded and the aqueous layer was extracted with acetonitrile (10.0 volume x T). All acetonitrile layers were combined, washed with brine (2.0 volume) and concentrated. Residual solvents were azeotropically removed with acetonitrile (8.0 volume x 2) to provide the crude product as a yellow solid (0.62 wt, 0.080 equivalent).

[000137] Crude compound AJ (1 weight, 1 volume) was suspended in IPA (6.0 volume) and heated to 80°C. The resulting solution was cooled to room temperature for 1 hour. The mixture was also cooled to 0°C and stirring was continued at 0°C for an additional hour. Precipitations were collected by filtration, washed with cold IPA (2.0 volume), and dried to provide compound AJ as a white powder (0.72 weight, 0.72 equivalent). 1H NMR (500 MHz, CDCI3): δ 4.37 (1H, dd, J=6.5, 5.0 Hz), 3.97-4.04 (1H, m), 3.88-3.89 (1H, m), 3.74-3.79 (1H, m), 3.42 (1H, dd, J=10.0, 7.0 Hz), 2.91-2.99 (1H, m ), 2.56 (1H, br), 2.37-2.41 (1H, m), 2.27 (1H, br), 2.05-2.11 (1H, m), 1.96- 2.00 (1H, m), 1.82 (1H, d, J=11.5Hz), 1.75 (1H, t, J=11.5Hz), 1.65-1.70 (1H , m), 1.54-1.61 (2H, m), 1.47-1.53 (1H, m), 1.32 (3H, d, J=7.0 Hz), 1.15- 1.24 (1H, m) 13 C NMR (125 MHz, CDCl 3 ): δ 122.93, 77.71, 77.00 (overlaid with chloroform signal), 73.60, 69.14, 68.45, 67 .04, 43.66, 40.38, 29.88, 28.85, 28.37, 22.48, 18.53 13 C NMR (125 MHz, acetone-d6) δ 122.60, 77.77, 77 .04, 73.32, 69.40, 68.34, 66.55, 44.02, 40.11, 29.93, 28.74, 28.16, 22.25, 17.95 LRMS (ESI) m/z found 289.95 [M+Na]+ Melting point 189°C Example 4: Synthesis of compound AK from compound AJ Scheme 14

[000138] Compound AJ (1 weight, 1 volume, 1 equivalent) was suspended in acetonitrile (5.00 volume) and cooled to 0°C. 2-Acetoxy-2-methylpropionyl bromide (0.938 weight, 0.656 volume) was added at a rate so that the internal temperature did not exceed 7°C. Upon complete addition, water (0.002 volume, 3 mol %) was added and stirring was continued at 0°C for an additional hour. The reaction mixture was diluted with MTBE (5.0 volume). After the internal temperature had dropped to 0°C, 10% by weight of aqueous NaHCO3 (5.0 volume, 3.4 equivalent) was carefully added with vigorous stirring keeping the internal temperature below 7°C and the resulting mixture was allowed to divide. . The organic layer was excluded and the aqueous layer was extracted with MTBE (5.0 volume). All organic layers were combined, washed sequentially with: 1) 10% by weight aqueous NaHCO3 (2.0 volume, 1.4 equivalent); 2) water (2.0 volume); 3) brine (2.0 volume), and concentrated to give crude compound AK as light brown oil (1.47 weight, 1.04 equivalent). The crude product was azeotropically dried with toluene (4 volume x 3) and used for the next reaction without purification. 1H NMR (500 MHz, CDCI3): δ 5.20 (1H, br), 4.38 (1H, dd, J=6.5, 3.5 Hz), 4.21-4.23 (1H, m ), 4.04 (1H, dd, J=10.0, 7.0 Hz), 3.79-3.83 (1H, m), 2.90-2.98 (1H, m), 2. 51-2.56 (2H, m), 2.30-2.34 (1H, m), 2.11-2.15 (1H, m), 2.07 (3H, s), 1.65- 1.71 (1H, m), 1.57-1.62 (3H, m), 1.49-1.55 (1H, m), 1.32 (3H, d, J=6.5 Hz) , 1.21-1.30 (1H, m) 13 C NMR (125 MHz, CDCl 3 ): δ 169.39, 122.79, 78.13, 75.49, 75.42, 73.76, 68.45 , 44.66, 43.48, 40.11, 29.48, 28.88, 28.38, 22.40, 21.12, 18.46 LRMS (ESI) m/z found 393.96 [M+Na] + . Example 5: Synthesis of Compound AL from Compound AJ

[000139] Compound AJ (1 weight, 1 volume, 1 equivalent) was suspended in acetonitrile (3.0 volume) and cooled to 0°C. 2-Acetoxy-2-methylpropionyl bromide (1.02 wt, 1.30 equivalent) was added at a rate so that the internal temperature did not exceed 2°C. Upon complete addition, a mixture of acetonitrile-water (water (0.0020 volume, 0.030 equivalent) and acetonitrile (0.020 volume)) was stirred and stirring was continued at 0°C for 2 hours. Under vigorous stirring, 10% by weight of aqueous NaHCO3 (5.0 volume) was added at a rate such that the internal temperature did not exceed 8°C (CO2 evolution). Toluene (4.3 weight, 5.0 volume) was added and vigorous stirring was continued for 3 minutes. The mixture was allowed to split and the organic layer was excluded. The aqueous layer was extracted with toluene (2.6 weight, 3.0 volume). All organic layers were combined and washed sequentially with: 1) 10% by weight aqueous NaHCO3 (3.0 volume); 2) water (2.0 volume).

[000140] The organic layer was transferred to a reactor and subjected to distillation under atmospheric pressure to remove 5 weights of solvent. Distillation included heating the organic layer to 90°C to remove the acetonitrile and then heating the mixture to about 110°C to remove the toluene. After cooling to 80°C, toluene (2.50 weight, 3 volume) was added followed by DBU (1.12 volume, 1.14 weight, 2.00 equivalent). The mixture was reheated to 100°C and stirred vigorously for 17 hours. The reaction mixture was cooled to 0°C and 1.00M aqueous HCl (4.5 volume, 1.2 equivalent) was added at a rate such that the internal temperature did not exceed 8°C. The resulting mixture was allowed to divide. The organic layer was excluded and the aqueous layer was extracted with toluene (1.73 weight, 2.0 volume). All organic layers were combined, washed sequentially with: 1) 1.00M aqueous HCl (0.50 volume, 0.13 equivalent); 2) 10% by weight aqueous NaHCO3 (1.0 volume); 3) water (2.0 weight, 2.0 volume), and concentrates. Residual toluene was azeotropically removed with IPA (2.0 volume) to provide the crude product as a yellow solid. Crude compound AL was suspended in IPA (5.0 volume) and heated to 80°C. The resulting solution was cooled to 0°C over 2 hours and stirring was continued at 0°C for a further 30 minutes. The crystals were collected by filtration, washed with cold IPA (1 volume) followed by heptane (1 volume), and dried to provide compound AL as a white powder (0.64 weight, 0.59 equivalent). The mother liquor was concentrated and diluted with IPA-heptane (1:1 volume/volume, 1.0 volume). A white precipitate formed, collected by filtration, washed with: 1) IPA-heptane (1:1 volume/volume, 0.4 volume); 2) heptane (0.4 volume), and dried to provide additional compound AL (0.043 weight, 0.040 equivalent). Example 6: Synthesis of compound AL from compound AK Scheme 16

[000141] Compound AK (1 weight, 1 volume, 1 equivalent) was dissolved in toluene (5.0 volume). DBU (0.818 weight, 0.803 volume, 2.0 equivalent) was added at 23°C and the mixture was heated to 100°C. Upon complete consumption of compound AK, the reaction mixture was cooled to 10°C and 1M HCl (3.5 volume, 1.3 equivalent) was added. The resulting mixture was stirred vigorously for 5 minutes and allowed to divide. The organic layer was excluded and the aqueous layer was extracted with MTBE (5.0 volume). All organic layers were combined, washed sequentially with: 1) water (2.0 volume); 2) 10% by weight NaHCO3 solution (2.0 volume); 3) water (2.0 volume), and concentrated to give the mixture of water and light brown oil. Residual water was azeotropically removed with heptane (3.0 volume x 3) to provide crude compound AL as yellow solid (0.65 wt, 0.83 equivalent) 1 H NMR (500 MHz, CDCI3): δ 6.16 ( 1H, d, J=10 Hz), 5.60-5.63 (1H, m), 5.01-5.02 (1H, m), 4.34-4.36 (1H, m), 3 .80-3.85 (1H, m), 3.42 (1H, dd, J=5.0, 2.0 Hz), 2.93-3.01 (1H, m), 2.53-2 .57 (1H, m), 2.07-2.12 (1H, m) 2.03 (3H, s), 1.56-1.72 (4H, m), 1.49-1.55 ( 1H, m), 1.32 (3H, d, J=6.5 Hz), 1.22-1.30 (1H, m) 13 C NMR (125 MHz, CDCl3): δ 170.10, 142.16 , 122.82, 122.42, 79.43, 75.26, 74.81, 69.52, 68.48, 40.36, 29.62, 28.90, 28.77, 22.49, 21 .26, 18.54 LRMS (ESI) m/z found 314.04 [M+Na]+ Melting point 92°C Example 7: Synthesis of compound AM from compound AL Scheme 17

[000142] Compound AL (1 weight, 1 volume, 1 equivalent) was dissolved in Me°H-DCM (5:3 volume/volume, 8.0 volume) and cooled to -47°C. °3 was bubbled into the mixture maintaining an internal temperature below -42°C. Upon complete consumption of the AL compound, excess °3 was purged by N2 bubbling until the peroxide test for the reactor output was negative. The reaction mixture was then allowed to warm to -25°C and NaBH4 (0.0753 weight, 0.580 equivalent) was added while maintaining an internal temperature below -17°C. Upon complete addition, the mixture was stirred at -20°C for 1 hour and then allowed to warm to 0°C. NaBH4 (granules, 0.0753 weight, 0.580 equivalent) was added (while maintaining an internal temperature below 3°C) and stirring was continued at 0°C for one hour. K2CO3 (0.712 weight, 1.50 equivalent) was added at 0°C and the reaction was allowed to warm to 20°C. Upon complete consumption of the acetate intermediate (approximately 4 hours), the reaction mixture was cooled to 0°C and 10 wt% aqueous HCl (5.1 wt, 4.1 equivalent) was added with vigorous stirring to adjust the pH. to 6-7.

Composto AM[000143] The resulting biphasic mixture was partially concentrated (to approximately 5.6 weight) by stripping volatiles, re-diluted with water-THF (1:1 volume/volume, 4.0 volume), and cooled to 15°C. NaIO 4 (1.47 weight, .00 equivalent) was added and the resulting suspension was stirred at 20°C until complete consumption of triol (approximately 3 hours). The reaction mixture was then diluted with EtOAc (6.0 volume), stirred vigorously for 5 minutes, and filtered through a pad of celite (2 weight). The filtrate (FI) was separated and excluded and the filter cake was washed with EtOAc-EtOH (9:1 volume/volume, 4.0 volume) (filtrate: F-2). NaCl (1.0 wt) was added to the IF and the resulting mixture was stirred vigorously for 5 minutes and allowed to divide. The organic layer was excluded and the aqueous layer was extracted with F-2. All organic layers were combined, washed sequentially with: 1) 10 wt% aqueous Na2S2O3 (1.0 wt); 2) water (1.0 volume); 3) water (1.0 volume) and concentrated to give a white solid. Residual water and solvents were azeotropically removed with EtOAc (6.0 volume x 3) to provide the crude product as a white solid (0.84 wt, 0.96 equivalent). The crude was suspended in heptane-EtOAc (1:1 volume/volume, 3.5 volume) and heated to 80°C. The resulting solution was cooled to room temperature for 2 hours (precipitation started at -65°C). The mixture was also cooled to 0°C and stirring was continued for an additional hour. The crystals were collected by filtration, washed with cold heptane-EtOAc (1:1 volume/volume, 1.8 volume), and dried under N 2 /vacuum to give compound AM as a white powder (0.58 wt., 0.67 equivalent). The mother liquor was concentrated, suspended in heptane-EtOAc (4:3 volume/volume, 0.9 volume), and heated to 80°C. The resulting clear solution was cooled to 20°C for 2 hours. The mixture was also cooled to 0°C and stirring was continued for an additional hour. The crystals were collected by filtration, washed with cold heptane-EtOAc (4:3 volume/volume, 0.50 volume) and dried under N 2 /vacuum to provide additional compound AM as a white powder (0.068 weight, 0.08 equivalent) . 1H NMR (for larger anomer, 500 MHz, CDCI3): δ 4.96 (1H, s), 4.17 (1H, dd, J=6.0, 3.5 Hz), 3.90 (1H, d , J=9.5 Hz), 3.82-3.74 (2H, m), 3.41 (1H, dd, J=10, 3.0 Hz), 3.01 (1H, s), 2 .95-2.85 (1H, m), 2.51-2.45 (1H, m), 2.22-2.15 (1H, m), 1.72-1.64 (1H, m) , 1.63-1.48 (3H, m), 1.29 (3H, d, J=13 Hz), 1.30-1.18 (1H, m) 13 C NMR (for larger anomer, 125 MHz, CDC13): δ 122.81, 92.46, 77.17, 75.70, 72.43, 71.18, 68.36, 40.28, 29.82, 28.70, 28.40, 22, 42.18.52 LRMS (ESI) m/z found 307.99 [M+MeOH+Na]H Melting point 116°C Example 8: Synthesis of compound AN from compound AM Scheme 18

AM compound

[000144] Compound AM (1 weight, 1 volume, 1 equivalent) was suspended in acetonitrile (4.0 volume) and cooled to 10°C. LiCl (0.184 weight, 1.10 equivalent) was added followed by N5N-diisopropylethylamine (0.825 volume, 1.20 equivalent). After the internal temperature dropped to 10°C, trimethyl phosphonoacetate (0.703 volume, 1.10 equivalent) was added at a rate such that the internal temperature did not exceed 13°C. Upon complete addition, the reaction was stirred at 10°C for one hour and then allowed to warm to 20°C. Stirring was continued at 20°C until complete consumption of compound AM. The reaction mixture was diluted with MTBE (8.0 volume) and cooled to 0°C. 1.00 M aqueous HCl (5.0 Volume, 1.5 equivalent) was added with vigorous stirring while keeping the internal temperature below 8°C and the resulting biphasic mixture was allowed to divide. The organic layer was excluded and the aqueous layer was extracted with MTBE (4.0 volume & 2.0 volume). All organic layers were combined, washed sequentially with: 1) 10% by weight aqueous NaHCO3 (3.0 volume); 2) water (2.0 volume) and concentrated to give compound AN as a pale yellow oil (E:Z ~20:1). 1H NMR (500 MHz, CDCI3): δ 6.87 (1H, dd, J=16.0, 3.5 Hz), 6.02 (1H, dd, J= 16.0, 1.5 Hz), 4.81-4.86 (1H, m), 4.02 (1H, dd, J=9.0, 6.0 Hz), 3.86-3.91 (1H, m), 3.73 ( 3H, s), 3.46-3.52 (2H, m), 2.87-2.94 (1H, m), 2.51 (1H, dd, J= 14.0, 10.0 Hz) , 2.14 (1H, dd, J=7.5, 5.5 Hz), 1.92-1.98 (1H, m), 1.75-1.83 (1H, m), 1.66 -1.74 (3H, m), 1.61-1.45 (1H, m), 1.33 (3H, d, J=7.0 Hz), 1.27-1.35 (1H, m ) 13 C NMR (125 MHz, CDCl 3 ): δ 166.95, 148.24, 123.08, 120.00, 84.03, 74.31, 74.25, 67.85, 67.77, 51.85 , 40.23, 35.52, 26.80, 24.18, 22.27, 18.30 LRMS (ESI) m/z found 332.05 [M+Na]+ Example 9: Synthesis of compound AO from of the compound NA Scheme 19

[000145] A reactor was charged with PtO2 (0.73% by weight, 1.0 mol%) under an atmosphere of N2. A solution of compound AN in MeOH (10.0 volume) was added under N 2 . The resulting suspension was cooled to 15°C and stirred under an atmosphere of 104 kPa (1.04 bar) H 2 . After two hours, the reaction was heated to 20°C and stirring was continued until complete consumption of compound AN. The reaction mixture was filtered through a pad of celite (1 weight) and the filter cake was washed with MeOH (5.0 volume). The filtrate was concentrated and residual MeOH was azeotropically removed with anhydrous DCM (3.0 volume x 2) to provide compound AO as a gray oil (1.06 weight, 1.05 equivalent). The crude product was used for the next reaction without purification. 1H NMR (500 MHz, CDCI3): δ 4.18-4.23 (1H, m), 3.82-3.91 (2H, m), 3.67 (3H, s), 3.53 (2H , d, J = 6.5 Hz), 2.86-2.93 (1H, m), 2.40-2.46 (1H, m), 2.31-2.38 (2H, m), 2.17 (1H, t, J= 7.0 Hz), 1.85-1.92 (1H, m), 1.591.84 (6H, m), 1.49 (1H, dd, J= 14, 0.5.5 Hz), 1.32 (3H, d, J=7.5 Hz), 1.23-1.30 (1H, m) 13 C NMR (125 MHz, CDCl3): δ 173.90, 123.10, 84.23, 74.90, 73.28, 68.31, 67.73, 51.81, 40.28, 35.99, 31.75, 30.78, 27.12, 24, 03, 22.27, 18.32 LRMS (ESI) m/z found 334.08 [M+Na]+ Example 10: Synthesis of compound AF from compound AO Scheme 20

[000146] Compound AO (1 weight, 1 volume, 1 equivalent) was dissolved in DCM (4.50 volumes). TEA (1.16 volume, 0.84 weight, 2.60 equivalent) was added and the mixture was cooled to -70°C. A solution of Tf2O (0.702 volume, 1.30 equivalent) in DCM (1.50 volume) was added at a rate so that the internal temperature did not exceed -65°C. Upon complete addition, the reaction was stirred at -73°C for 1.5 hours, allowed to warm to -20°C, and stirred at -20°C for a further 30 minutes.

[000147] DMF (3.0 volume) was added and the mixture was allowed to warm to 0°C. NaI (0.674 weight, 1.40 equivalent) was added and the reaction was also heated to 23°C. Upon complete consumption of the triflate (The compound AT), the reaction mixture was diluted with heptane (8.0 volume) and cooled to 0°C. Water (9.0 volume) was added while maintaining an internal temperature below 10°C. The resulting biphasic mixture was stirred vigorously for 3 minutes and then allowed to divide. The organic layer was excluded and the aqueous layer was extracted with MTBE (6.0 volume). All organic layers were combined, washed sequentially with: 1) 1.00M aqueous HCl (5.00 volume, 1.56 equivalent); 2) 10% by weight aqueous NaHCO3 (2.0 volume); 3) 10% by weight aqueous Na2S2O3 (2.0 volume), 4) water (2.0 volume); 5) water (2.0 volume) and concentrates. The residue was dissolved in MTBE (6.0 volume) and silica gel (1.0 weight) was added. The resulting suspension was stirred at 22°C for 5 minutes and then filtered. The silica gel on the filter was washed with MTBE (8.0 volume) and the filtrate was concentrated to give the crude product as a reddish solid (1.35 weight, 1.00 equivalent).

[000148] Compound AF (1.35 weight, 1.00 equivalent) was suspended in MTBE (1.4 volume) and heated to 45°C. Heptane (2.8 volume) was added while maintaining an internal temperature between 40°C and 45°C. The resulting clear solution was cooled to 22°C over 1 hour and then stirred at 22°C for 2 hours. The mixture was cooled to 0°C and stirring was continued for a further 2 hours. Precipitations were collected by filtration, washed with pre-cooled (0°C) heptane-MTBE (1:3 volume/volume, 2.8 volume) and dried under N2/vacuum for one hour to provide compound AF as a brown powder. clear (0.98 weight, 0.72 equivalent). The mother liquor was concentrated and redissolved in MTBE (0.33 volume). Heptane (0.33 volume) was added and the resulting clear solution was cooled to 0°C. A very small amount of compound AF crystal (from the 1st crop) was added for seeding and stirring was continued at 0°C for 15 hours. Precipitations were collected by filtration, washed with pre-cooled (0°C) heptane-MTBE (1:2 volume/volume, 0.33 volume), and dried under N2/vacuum for 1 hour to provide additional compound AF as light brown powder (0.046 weight, 0.034 equivalent). Compound AT 1H NMR (500 MHz, CDCl 3 ): δ 4.46 (1H, d, J= 10.5 Hz), 4.38 (1H, d, J= 10.5 Hz), 4.21-4, 26 (1H, m), 3.89 (1H, dd, J=8.5, 6.0 Hz), 3.81-3.86 (1H, m), 3.68 (3H, s), 2 .93-3.00 (1H, m), 2.41-2.50 (2H, m), 2.33-2.39 (1H, m), 1.91-1.97 (1H, m) , 1.64-1.92 (6H, m), 1.45 (1H, dd, J=14.5, 5.5 Hz), 1.25-1.35 (1H, m), 1.32 (3H, d, J=7.0 Hz) 13 C NMR (125 MHz, CDCl3 ) δ 173.62, 122.86, 117.51, 81.84, 78.54, 74.57, 73.08, 68 .63, 51.94, 40.16, 35.28, 31.77, 30.64, 27.13, 23.95, 22.33, 18.42 LRMS (ESI) m/z found 446.12 [ M+Na]+ Compound AF 1H NMR (500 MHz, CDCl 3 ): δ 4.21-4.26 (1H, m), 3.78-3.83 (2H, m), 3.67 (3H, s ), 3.44 (1H, d, J= 10.0 Hz), 3.37 (1H, d, J= 10.0 Hz), 2.993.03 (1H, m), 2.49 (1H, dd , J= 9.0, 8.5 Hz), 2.42-2.47 (1H, m), 2.322.38 (1H, m), 1.80-1.89 (3H, m), 1, 63-1.75 (5H, m), 1.33 (3H, d, J= 7.5 Hz), 1.24-1.30 (1H, m) 13 C NMR (125 MHz, CDCl 3 ): δ 173 .74, 122.89, 81.75, 76.07, 75.10, 68.24, 51.86, 40.52, 39.00, 31.78, 30.75, 27.09, 24.36 , 22.53, 18.72, 18.51 LRMS (ESI) m/z found 444.02 [M+Na]' Melting point 69.5°C. Example 11: synthesis of compound AP from compound AF Scheme 21

[000149] Compound AF (1 weight, 1 volume, 1 equivalent) was dissolved in toluene (5.0 volume) and cooled to 10°C. LIbH4 (2.0M solution in THF, 2.4 volume, 2.0 equivalent) was added and stirring was continued at 20°C for 18 hours. The reaction mixture was cooled to 0°C and slowly poured into a pre-cooled (0°C) mixture of EtOAc (6 volume) and 1.0M aqueous HCl (6.0 volume, 2.5 equivalent) with stirring. vigorous. The reactor was rinsed with EtOAc (2 volume) and the resulting wash was combined with the biphasic mixture. The organic layer was excluded and the aqueous layer was extracted with EtOAc (5.0 volume). All organic layers were combined, washed sequentially with: 1) 10% by weight aqueous NaHCO3 (2 volume); 2) water (2 volume) and concentrated. Residual water was azeotropically removed with toluene (5 volumes x 2) to provide compound AP (0.93 weight, 0.89 equivalent). 1H NMR (500 MHz, CDCI3): δ 4.24-4.30 (1H, m), 3.86 (1H, dd, J=8.5, 6.0 Hz), 3.78-3.83 (1H, m), 3.62-3.68 (2H, m), 3.44 (1H, d, J= 10.5 Hz), 3.38 (1H, d, J= 10.5 Hz) , 2.99-3.04 (1H, m), 2.51 (1H, dd, J= 14.0, 8.5 Hz), 2.06 (1H, t, J= 6.0 Hz), 1.86-1.92 (1H, m), 1.59-1.78 (9H, m), 1.33 (3H, d, J=7.0 Hz), 1.24-1.31 ( 1H, m) 13 C NMR (125 MHz, CDCl 3 ): δ 122.94, 82.70, 76.27, 76.25, 68.42, 62.77, 40.50, 39.08, 33.72, 29.67, 27.25, 24.59, 22.55, 19.08, 18.51 LRMS (ESI) m/z found 416.02 [M+Na]+ Example 12: Synthesis of compound AU from compound AP Scheme 22

[000150] An inert reactor was charged with Zn powder (2.5 weight, 15 equivalent) at 23°C. MeOH (5.0 volume) was added followed by AcOH (2.0 volume, 14 equivalents). The resulting suspension was stirred at 23°C for 20 minutes and then cooled to 0°C. A solution of compound AP (1 weight, 1 volume, 1 equivalent) in MeOH (5.0 volume) was added and vigorous stirring was continued at 0°C for 3 hours and at 23°C for 1.5 hours. The reaction mixture was diluted with EtOAc (20 volume). Excess Zn powder was filtered off and rinsed with EtOAc (10 volume). The filtrate was washed with 1.00M aqueous HCl (10 volume). The organic layer was excluded and the aqueous layer was extracted with EtOAc (20 volume). All organic layers were combined, washed sequentially with: 1) 10% by weight aqueous NaHCO3 (20 volume); 2) 10% by weight aqueous Na2S2O3 (8 volume); 3) brine (8 volume), and concentrated to give the crude product as a pale yellow oil. The crude was purified by flash column chromatography (Biotage, heptane-EtOAc 3:7^2:8^0:10) to give compound AU (0.62 wt, 0.90 equivalent) as a pale yellow oil. 1H NMR (500 MHz, hCDC): δ 5.01 (1H, s), 4.85 (1H, s), 4.41 (1H, br), 4.08-4.12 (1H, m), 3.93 (1H, br), 3.60-3.68 (2H, m), 3.12 (1H, br), 2.973.05 (1H, m), 2.69-2.73 (1H, m). m), 2.45 (1H, br), 2.29-2.33 (1H, m), 1,531.80 (10H, m), 1.33 (3H, d, J=7.5 Hz) 13C NMR (125 MHz, CDCl 3 ): δ 150.95, 123.29, 105.49, 79.66, 77.69, 68.79, 62.84, 41.83, 39.03, 34.33, 32 .11, 30.89, 29.80, 22.93, 18.61 LRMS (ESI) m/z found 289.96 [M+Na]+ Example 13: Synthesis of compound AR from compound AU Scheme 23

[000151] Compound AU (1 weight, 1 volume, 1 equivalent) was dissolved in MeOH (2.0 volume). The mixture was cooled to 0°C and HCl (6M solution in IPA, 2.0 volume, 13 equivalents) was added. The reaction was allowed to warm to 23°C and stirring was continued until complete consumption of compound AU (approximately 20 hours). The reaction mixture was diluted with toluene (8.0 volume) and water (4.0 volume) and the resulting biphasic mixture was heated at 60°C for 3 hours. After cooling, the organic layer was excluded and the aqueous layer was extracted with EtOAc (8.0 volume). All organic layers were combined, washed sequentially with: 1) 10% by weight aqueous NaHCO3 (2.0 volume); 2) brine (2.0 volume); 3) water (2.0 volume), and concentrated to give crude AR compound (0.93 wt, 0.93 equivalent) as a pale yellow oil. The crude product was azeotropically dried with toluene (8 volume x 2) and used for the next reaction without purification. 1H NMR (500 MHz, CDCI3): δ 4.98-4.99 (1H, m), 4.84-4.85 (1H, m), 4.49-4.54 (1H, m), 4 .39 (1H, d, J=10.5 Hz), 4.00-4.05 (1H, m), 3.593.68 (2H, m), 2.63-2.72 (2H, m), 2.56-2.62 (1H, m), 2.25-2.30 (1H, m), 2.08-2.14 (1H, m), 1.97-2.02 (1H, m ), 1.52-1.82 (7H, m), 1.26 (3H, d, J=7.5 Hz), 1.24-1.34 (1H, m) 13 C NMR (125 MHz, CDCl3 ) δ 180.34, 151.14, 105.39, 79.71, 78.84, 77.54, 62.72, 39.02, 35.69, 34.15, 32.19, 32.16, 31.50, 29.64, 16.02 LRMS (ESI) m/z found 290.99 [M+Na]+ Example 14: Synthesis of compound AR from compound AH Scheme 24

[000152] Compound AR (1 weight, 1 volume, 1 equivalent) was dissolved in DMF (2.0 volumes) and imidazole (0.330 weight, 1.30 equivalent) was added at 23°C (endothermic). Upon complete dissolution of imidazole, the mixture was cooled to 10°C and tert-butylchlorodiphenylsilane (TBDPSCl, 0.969 volume, 1.02 weight, 1.00 equivalent) was added. The reaction mixture was stirred at 10°C for 1 hour, allowed to warm to 23°C, and stirred until complete consumption of AR compound (approximately 3 hours). The reaction mixture was diluted with Heptane-MTBE 1:1 (8.0 volume) and cooled to 10°C. Water (8.0 volume) was added with vigorous stirring and the resulting mixture was allowed to divide. The aqueous layer was excluded. The organic layer was also washed with water (1.0 volume) and concentrated. Residual water and solvents were azeotropically removed with toluene (8.0 volume x 2) to provide compound AH as a colorless oil (1.98 wt, 100%). The crude product was used for the next reaction without purification. 1H NMR (500 MHz, CDCI3): δ 7.65-7.67 (4H, m), 7.36-7.44 (6H, m), 4.99 (1H, dd, J=4.0, 2.5 Hz), 4.84 (1H, dd, J= 4.0, 2.5 Hz), 4.50-4.55 (1H, m), 4.35 (1H, d, J=9 .0 Hz), 3.97-4.02 (1H, m), 3.66-3.70 (2H, m), 2.66-2.71 (1H, m), 2.61-2, 66 (1H, m), 2.22-2.27 (1H, m), 2.08-2.14 (1H, m), 1.97-2.03 (1H, m), 1.50- 1.81 (8H, m), 1.28 (3H, d, J=7.5 Hz), 1.04 (9H, s) 13 C NMR (125 MHz, CDCl3): δ 180.18, 151.68 , 135.79 (4C), 134.21 (2C), 129.84 (2C), 127.89 (4C), 105.27, 79.58, 78.83, 77.38, 64.02, 39 .08, 35.78, 34.20, 32.29, 31.76, 31.60, 29.31, 27.16 (3C), 19.48, 16.15 LRMS (ESI) m/z found 529.26 [M+Na]+ Example 15: Synthesis of compound AV from compound AH Scheme 25

[000153] An inert reactor was charged with N,O-dimethylhydroxylamine hydrochloride (0.298 weight, 1.55 equivalents). DCM (2.0 volume) was added and the resulting suspension was cooled to -5°C. Trimethylaluminium (2.0 M solution in toluene, 1.48 volume, 1.50 equivalent) was slowly added at a rate so that the internal temperature did not exceed 3°C. Upon complete addition, the mixture was stirred at 0°C for 30 minutes. A solution of compound AH (1 weight, 1 volume, 1 equivalent) in DCM (3.0 volume) was added at a rate so that the internal temperature did not exceed 5°C and stirring was continued at 0°C until the complete consumption of AH compound. Another reactor was charged with 20 wt% Rochelle salt (10 weights) and MTBE (10 volumes), and cooled to 0°C. The reaction mixture was transferred into the pre-cooled biphasic mixture while keeping the internal temperature below 5°C. The resulting mixture was vigorously stirred at 0°C for 30 minutes and then allowed to divide. The organic layer was excluded and the aqueous layer was extracted with MTBE (10 volumes). All organic layers were combined, washed sequentially with: 1) 20% by weight Rochelle salt solution (5 weights); 2) water (3 volumes); 3) brine (2 volumes), and concentrated to give the crude product as a pale yellow oil. The crude product was azeotropically dried with toluene (5 volumes x 2) and used for the next reaction without purification.

[000154] The crude hydroxyamide was dissolved in DMF (2.0 volume) and cooled to 10°C. Imidazole (0.161 weight, 1.20 equivalent) was added followed by TBSCl (0.297 weight, 1.00 equivalent). The reaction was stirred at 15°C for 2 hours, allowed to warm to 23°C, and stirred until complete consumption of the hydroxyamide intermediate. The reaction mixture was diluted with heptane-MTBE 1:1 (10 volumes) and cooled to 0°C. Water (8 volume) was added and the resulting biphasic mixture was vigorously stirred and allowed to divide. The organic layer was excluded and the aqueous layer was extracted with heptane-MTBE (1:1 volume/volume, 8.0 volumes). All organic layers were combined, washed sequentially with: 1) water (3.0 volumes); 2) brine (3.0 volumes), and concentrated to provide crude AV compound (1.35 wt, 0.99 equivalent) as a pale yellow oil.

EQUIVALENTS

[000155] Those skilled in the art will recognize, or be able to verify using no more than a routine experiment, numerous equivalents to the specific procedures described here. Such equivalents are considered to be within the scope of the present invention and are encompassed by the following claims. The contents of all references, patents, and patent applications cited throughout this application are hereby incorporated by reference. Appropriate components, processes, and methods of those patents, applications, and other documents may be selected for the present invention and embodiments thereof.

Claims (62)

1. Method of obtaining a diastereomerically pure composition of a compound of formula (I), characterized in that it comprises: crystallizing said compound of formula (I) from a mixture of diastereomers to obtain a composition in which the proportion of said compound of formula (I) to the compound having the opposite stereochemistry at the chiral center indicated with an asterisk is at least 8:1, wherein said compound of formula (I) is:

wherein: z is a single or double bond, provided that when z is a double bond, X2 is C and Y1 is hydrogen; and provided that when z is single bond, X2 is CH or O; X1 is O, S, or CN, provided that when X1 is CN or S, X2 is O; Y1 is a halide, hydrogen or O-L2, or absent when X2 is O; L1 and L2 are independently hydrogen or a group selected from C1-C12 alkylcarbonyl, C1-C6 alkyl, C1-C15 alkyl silyl, C6-C10 aryl-(C1-C6)alkyl, carbonate, C1-C6-(C1)alkoxy -C6) alkyl, C1-C6 alkyl ester, benzoyl, and t-butyldiphenylsilyl, or L1 and L2 together are C1-C6 cyclic acetal, C3-C7 cyclic ketal, cyclic carbonate, benzylidene, or pyran, provided that when X1 for CN, L1 is absent; or a salt thereof. 2. Method according to claim 1, characterized in that at least one of L1 and L2 is a group selected from C1-C12 alkylcarbonyl, C1-C6 alkyl, C1-C15 alkyl silyl, C6-C10 (C1-aryl) -C6) alkyl, carbonate, C1-C6 alkoxy-(C1-C6) alkyl, and C1-C6 alkyl ester; or L1 and L2 together are C1-C6 cyclic acetal, C3-C7 cyclic ketal, or cyclic carbonate. 3. Method according to claim 1, characterized in that at least one of L1 and L2 is a group selected from C1-C6 alkyl silyl, C1-C6 alkyl, benzoyl and C1-C8 alkyl carbonyl. 4. Method according to claim 1, characterized in that at least one of L1 and L2 is a group selected from methoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, methyl, t-butyl, 3 ,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, and trityl, or L1 and L2 together are cycloheptylidine. A method according to claim 1, characterized in that at least one of L1 and L2 is C1 alkyl carbonyl, or L1 and L2 together are acetonide, benzylidene, pyran, cyclohexylidene, or cyclopentylidene. 6. Method according to claim 1, characterized in that Y1 is O-L2; X1 is O or S; and L1 and L2 together form a C4-C7 alkyl ring with a ring member covalently bonded to either the O of Y1 or X1. 7. Method according to claim 1, characterized in that said ratio is at least 20:1. 8. Method according to claim 1, characterized in that said compound of formula (I) is of formula (Ib):

wherein L1a and L1b are independently hydrogen or a group selected from C1-C6 alkyl, C6-C10 aryl-(C1-C6) alkyl, C1C10 alkyl silyl and C1-C6 alkyl ester, or L1a and L1b together are C1- C6 cyclic acetal, C3-C7 cyclic ketal or cyclic carbonate. Method according to claim 8, characterized in that L1a and L1b are independently C1-C6 alkyl, C6C10 aryl (C1-C6) alkyl, C1-C10 alkyl silyl, or C1-C6 alkyl ester, or L1a and L1b together are C1-C6 cyclic acetal, C3-C7 cyclic ketal, or cyclic carbonate. 10. Method according to claim 8, characterized in that L1a and L1b together are cyclohexylidine. 11. Method according to claim 1, characterized in that said compound of formula (I) is selected from the group consisting of:

12. Method according to claim 1, characterized in that heptane is present as an anti-solvent. 13. Method according to claim 12, characterized in that a co-solvent selected from the group consisting of tert-butyl methyl ether and isopropanol is also present. 14. Method according to claim 1, characterized in that a base is added. 15. Method according to claim 14, characterized in that said base is potassium tert-butoxide. A method according to claim 1, characterized in that said composition comprises a ratio of compound of formula (I) to compound of formula (Ie) of at least 30:1, wherein said compound of formula ( ie) is:

17. A method of preparing a diastereomerically pure composition of a compound of formula (Ib) from a compound of formula (Ia), wherein the compound of formula (Ia) is:

and the compound of formula (Ib) is:

wherein L1a and L1b are independently hydrogen or a group selected from the group consisting of C1-C6 alkyl, C6-C10 aryl-(C1-C6) alkyl, C1-C10 alkyl silyl and C1-C6 alkyl ester; or L1a and L1b together are C1-C6 cyclic acetal, C3-C7 cyclic ketal or cyclic carbonate, provided that L1a of formulas (Ia) and (Ib) are the same and Llb of formulas (Ia) and (Ib) are the same , said method being characterized in that it comprises: reacting the compound of formula (Ia) under alkylation conditions to form a mixture comprising the compound of formula (Ib) and diastereomers thereof; and crystallizing the compound of formula (Ib) from the mixture to obtain a composition in which the ratio of said compound of formula (Ib) to the compound having the opposite stereochemistry at the chiral center indicated with an asterisk is at least 8:1 . 18. Method according to claim 17, characterized in that said alkylation conditions comprise an aprotic solvent, a base, and a C1 alkyl halide or methyl sulfonate. 19. Method according to claim 18, characterized in that said aprotic solvent is tetrahydrofuran, toluene, or t-butyl methyl ether. 20. Method according to claim 17, characterized in that the crystallization comprises the addition of a base. 21. Method according to claim 20, characterized in that said base is lithium diisopropyl amide, potassium-hexamethyldisilazane, or potassium t-butoxide. 22. Method according to claim 17, characterized in that said ratio is at least 20:1. A method according to claim 17, characterized in that L1a and L1b are each selected from C1-C6 alkyl, C6-C10 aryl (C1-C6) alkyl, C1-C10 alkyl silyl, and C1- C6 alkyl ester; or L1a and L1b together are C1-C6 cyclic acetal, C3-C7 cyclic ketal, or cyclic carbonate. 24. Method according to claim 17, characterized in that L1a and L1b together are cyclohexylidine. 25. Method of obtaining a diastereomerically pure composition of a compound of formula (II), characterized in that it comprises: crystallizing said compound of formula (II) from a mixture of diastereomers to obtain a composition in which the proportion of said compound of formula (II) to the compound having the opposite stereochemistry at the chiral center indicated with an asterisk is at least 8:1, wherein said compound of formula (II) is:

where: c is a single or double bond, provided that when c is a double bond m is 0 and Y3 is O or CHCO2-L3, and provided that when c is a single bond, m is 0 or 1, Y3 is CH2O - L3, CH2CO2-L3 or CH2CH2O-L3; Y2 is R-SO2-O-, where R is C1-C4 alkyl or C6 aryl; O-L4 or a halide; L4 is hydrogen or a group selected from C1-C12 alkylcarbonyl, C1-C6 alkyl, C1-C15 alkyl silyl, C6-C10 aryl-(C1-C6) alkyl, carbonate, C1-C6 alkoxy-(C1-C6) alkyl and t-butyldiphenylsilyl; and L3 is hydrogen or a group selected from C1-C12 alkylcarbonyl, C1-C10 alkyl, C6-C10 aryl, C1-C15 alkyl silyl, C6-C10 aryl-(C1-C6)alkyl, carbonate, C1-C6-alkoxy-( C1-C6) alkyl and t-butyldiphenylsilyl; and L5 is hydrogen or a group selected from C1-C12 alkylcarbonyl, C1-C6 alkyl, C1-C15 alkyl silyl, C1-C6 aryl-(C1-C6) alkyl, carbonate, C1-C6 alkoxy-(C1-C6) alkyl and t-butyldiphenylsilyl; or L3 and L5 together are C1-C6 cyclic acetal, C3-C7 cyclic ketal, benzylidene, cycloheptylidine or cyclic carbonate; or a salt thereof. Method according to claim 25, characterized in that at least one of L3 and L5 is a group selected from C1-C12 alkylcarbonyl, C1-C6 alkyl, C1-C15 alkyl silyl, C6-C10 aryl (C1- C6) alkyl, carbonate, and C1-C6 alkoxy-(C1-C6) alkyl; or L3 and L5 together are C1-C6 cyclic acetal, C3-C6 cyclic ketal, or cyclic carbonate. Method according to claim 25, characterized in that L4 is a group selected from C1-C12 alkylcarbonyl, C1-C6 alkyl, C1-C15 alkyl silyl, C6-C10 aryl (C1-C6) alkyl, carbonate, and C1-C6 alkoxy-(C1-C6) alkyl. 28. Method according to claim 25, characterized in that L3, L4, or L5 is a group selected from methoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, methyl, t-butyl, 3, 4-dimethoxybenzyl, p-methoxybenzyl, benzyl, and trityl; or L3 and L5 together are acetonide, benzylidene, cyclopentylidene, cyclohexylidine or cycloheptylidine. 29. Method according to claim 25, characterized in that Y3 is CH2CO2-L3, and L3 is C1-C10 alkyl, C6-C10 aryl-C1-C6 alkyl, or C6-C10 aryl. 30. Method according to claim 25, characterized in that L3 is methyl. 31. Method according to claim 25, characterized in that L3 and L5 together are a C1-C6 cyclic acetal or a C3-C7 cyclic ketal. 32. Method according to claim 25, characterized in that the crystallization comprises dissolving the compound of formula (II) in a polar solvent. 33. Method according to claim 32, characterized in that said polar solvent is tert-butyl methyl ether. 34. Method according to claim 32, characterized in that it also comprises adding an anti-solvent. 35. Method according to claim 25, characterized in that said ratio is at least 20:1. A method according to claim 25, characterized in that said composition comprises a ratio of compound of formula (II) to compound of formula (IIb) of at least 30:1 or more, wherein said compound of formula (IIb) is:

37. Method according to claim 25, characterized in that said compound of formula (II) is:

38. Composite, characterized by the fact that it presents the

z is a single or double bond, provided that when z is a double bond, X2 is C and Y1 is hydrogen; and provided that when z is single bond, X2 is CH or O; X1 is O, S, or CN, provided that when X1 is CN or S, X2 is O; Y1 is a halide, hydrogen or O-L2, or absent when X2 is O; and L1 and L2 are independently hydrogen or a group selected from C1-C12 alkylcarbonyl, C1-C6 alkyl, C1-C15 alkyl silyl, C6-C10 aryl-(C1-C6)alkyl, carbonate, C1-C6 alkoxy-(C1- C6) alkyl, C1-C6 alkyl ester, benzoyl, and t-butyldiphenylsilyl; or L1 and L2 together are C1-C6 cyclic acetal, C3-C7 cyclic ketal, cyclic carbonate, benzylidene, or pyran, provided that when X1 is CN, L1 is absent; or a salt thereof. 39. Compound according to claim 38, characterized in that at least one of L1 and L2 is a group selected from C1-C12 alkylcarbonyl, C1-C6 alkyl, C1-C15 alkyl silyl, C6-C10 aryl (C1- C6) alkyl, carbonate, C1-C6 alkoxy-(C1-C6) alkyl and C1-C6 alkyl ester; or L1 and L2 together are C1-C6 cyclic acetal, C3-C6 cyclic ketal, or cyclic carbonate. 40. Compound according to claim 38, characterized in that L1 and L2 is a group selected from methoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, methyl, t-butyl, 3,4-dimethoxybenzyl , p-methoxybenzyl, benzyl, and trityl; or L1 and L2 together are cycloheptylidine. 41. A compound according to claim 38, characterized in that at least one of L1 and L2 is C1 alkyl carbonyl, or L1 and L2 together are acetonide, benzylidene, pyran, cyclohexylidine or cycloheptylidine. 42. Compound according to claim 38, characterized in that at least one of L1 and L2 is C1-C10 alkyl silyl, C1-C6 alkyl, or C1-C8 alkyl carbonyl. 43. Compound according to claim 38, characterized in that Y1 is O-L2; X1 is O or S; and L1 and L2 together form a C4-C7 alkyl ring with a ring member covalently bonded to both the O of Y1 and X1. 44. Compound according to claim 38, characterized in that said compound is:

AD compound. 45. Compound according to claim 38, characterized in that said compound is selected from

AJ compound AK compound

Compound AL and Compound AM. 46. Compound according to claim 38, characterized in that said compound of formula (I) is of formula (Ib):

wherein L1a and L1B e are independently hydrogen or a group selected from C1-C6 alkyl, C6-C10 aryl-(C1-C6) alkyl, C1-C10 alkyl silyl and C1-C6 alkyl ester; or L1a and L1B together are C1-C6 cyclic acetal, C3-C7 cyclic ketal or cyclic carbonate. 47. A compound according to claim 46, characterized in that L1a and L1B are each selected from C1-C6 alkyl, C6-C10 aryl (C1-C6) alkyl, C1-C10 alkyl silyl and C1 ester -C6 alkyl; or L1a and L1b together are C1-C6 cyclic acetal, C3-C6 cyclic ketal, or cyclic carbonate. 48. Compound according to claim 46, characterized in that L1a and L1b together are cyclohexylidine. 49. Compound, characterized by the fact that it has the formula (II):

c is a single or double bond, provided that when c is a double bond, m is 0, and Y is O or CHCO2-L3, and provided that, when c is a single bond, m is 0 or 1, and Y3 is CH2O-L3, CH2CO2-L3 or CH2CH2O-L3; Y2 is R-SO2-O-, where R is C1-C4 alkyl or C6 aryl, O-L4 or a halide; L4 is hydrogen or a group selected from C1-C12 alkylcarbonyl, C1-C6 alkyl, C1-C15 alkyl silyl, C6-C10 aryl-(C1-C6) alkyl, carbonate, C1-C6 alkoxy-(C1-C6) alkyl and t-butyldiphenylsilyl; and L3 is hydrogen or a group selected from C1-C12 alkylcarbonyl, C1-C10 alkyl, C1-C15 alkyl silyl, C6-C10 aryl-(C1-C6) alkyl, carbonate, C1-C6 alkoxy-(C1-C6) alkyl and t-butyldiphenylsilyl; L5 is hydrogen or a group selected from C1-C12 alkylcarbonyl, C1-C6 alkyl, C1-C15 alkyl silyl, C1-C6 aryl-(C1-C6) alkyl, carbonate, C1-C6 alkoxy-(C1-C6) alkyl and t-butyldiphenylsilyl; or L3 and L5 together are C1-C6 cyclic acetal, C3-C7 cyclic ketal, cyclic carbonate or benzylidene; or a salt thereof. 50. Compound according to claim 49, characterized in that at least one of L3 and L5 is C1-C12 alkylcarbonyl, C1-C6 alkyl, C1-C15 alkyl silyl, C6-C10 aryl (C1-C6) alkyl, carbonate, or C1-C6 alkoxy-(C1-C6) alkyl; or L3 and L5 together are C1-C6 cyclic acetal, C3-C6 cyclic ketal, or cyclic carbonate. A compound according to claim 49, characterized in that L4 is C1-C12 alkylcarbonyl, C1-C6 alkyl, C1-C15 alkyl silyl, C6-C10 aryl (C1-C6) alkyl, carbonate, and C1-C6 (C1-C6) alkoxy alkyl. 52. A compound according to claim 49, characterized in that L3, L4, or L5 is a group selected from methoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, methyl, t-butyl, 3, 4-dimethoxybenzyl, p-methoxybenzyl, benzyl, and trityl, or L3 and L5 together are acetonide, benzylidene, cyclopentylidene, cyclohexylidine, or cycloheptylidine. 53. Compound according to claim 49, characterized in that Y3 is CH2CO2-L3 and L3 is C1-C10 alkyl, C6-C10 aryl-C1-C6 alkyl, or C6-C10 aryl. 54. Compound according to claim 49, characterized in that L3 is methyl. 55. A compound according to claim 49, characterized in that L3 and L5 together are a C1-C6 cyclic acetal or a C3-C7 cyclic ketal. 56. Compound according to claim 49, characterized in that Y2 is a halide. 57. Compound according to claim 56, characterized in that said halide is iodide. 58. Compound according to claim 49, characterized in that said compound is selected from the group consisting of:

AN compound AO compound

AF compound AP compound

59. Method to Produce Compound B-1939

characterized by the fact that it comprises: converting the AF compound

Compound AF in Compound AH

AH compound convert AH compound into AI compound

converting compound AI to compound B-1939. 60. Method according to claim 59, characterized in that: (a) compound AF is produced from compound AD:

(b) the AF compound is produced by a method as defined in claim 25. 61. Method according to claim 60, characterized in that said AD compound is produced by a method as defined in claim 1. 62. Composite, characterized by the fact that it is:

AF compound.